Castellino 2006

ANRV270-IY24-17 ARI 15 February 2006 1:34
Cooperation Between CD4+

and CD8+ T Cells: When,
Where, and How∗
Flora Castellino and Ronald N. Germain
Lymphocyte Biology Section, Laboratory of Immunology, National Institute of
Annu. Rev. Immunol. 2006.24:519-540. Downloaded from www.annualreviews.org
Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland

20892; email: rgermain@nih.gov
by University of Zaragoza on 03/31/13. For personal use only.
Annu. Rev. Immunol. Key Words

2006. 24:519–40
dendritic cells, T cell help, cell-mediated immunity, chemokines
The Annual Review of
Immunology is online at
immunol.annualreviews.org
Abstract
This article’s doi: Concepts of cell-cell interactions in adaptive immunity have alter-
10.1146/annurev.immunol.23.021704.115825 nated between the simple and the complex. The notion that one
Copyright
c 2006 by population of small, circulating lymphocytes is responsible for adap-
Annual Reviews. All rights tive immunity was sequentially supplanted by the concept of separate
reserved T and B lymphocyte populations that cooperate to produce IgG an-
∗
The U.S. Government tibody responses, by a three-cell model in which a myeloid APC
has the right to retain a initiates these cooperative lymphoid responses, by the recognition
nonexclusive, royalty-free
license in and to any of T cell subsets, and by the idea that CD8+ T cell subset responses
copyright covering this to graft antigens depend on CD4+ T cell subset activity. Simplic-
paper. ity was reintroduced with the revelation that CD8+ T cells can act
0732-0582/06/0423-0519$20.00 independently of CD4+ T cells against acute viral infections. The
pendulum has swung again toward complexity with recognition of
the distinct and conjoint contributions of innate stimuli, APCs, NK
and NKT cells, Tregs, and CD4+ helper T cells to CD8+ T cell
behavior during acute and chronic infections or as memory cells.
The renewed appreciation that multiple, sometimes rare cell types
must communicate during cell-mediated immune responses has led
to questions about how such interactions are orchestrated within or-
ganized lymphoid tissues. We review recent advances in deciphering
the specific contribution of CD4+ T cells to physiologically use-
ful CD8+ T cell responses, the signals involved in producing acute
effectors versus long-lived memory cells, and the mechanisms un-
derlying the cell-cell associations involved in delivery of such signals.
We propose a model based on these new findings that may serve as a
general paradigm for cellular interactions that occur in an inflamed
lymph node during the initiation of immune responses.
519
INTRODUCTION sire to understand better the basis for immune

dysfunction in individuals with defects in their
CD8+ T cells contribute to host defense dur-
CD4+ T cell population. After many years of
ing acute and chronic infection with viruses,
back and forth debate over whether interac-
intracellular bacteria, or single-cell as well as
tions between these two αβ T cell subsets are
multi-cellular parasites, and they also partic-
required in vivo for effective cell-mediated
ipate in the elimination of transformed cells
immunity, a consensus has begun to emerge
(1–8). There is thus a substantial interest at the
that distinguishes the requirements for acute
basic, translational, and clinical levels in un-
effector responses of CD8+ T cells from the
derstanding the antigens recognized by this
development of robust memory and in many
T cell subset, the processing pathways in-
circumstances assigns to CD4+ T cells a pri-
volved in the generation of these receptor
mary role in the latter rather than the for-
ligands, the cellular interactions that partici-
mer. Here, we review the evidence that CD4+
pate in facilitating and regulating responses by
T cell “help” (TH) has a key impact on CD8+

CD8+ T lymphocytes, and the soluble or cell-
memory cell formation and function, and de-
associated molecular signals that influence the
scribe the ongoing controversy about whether
differentiation and survival of this cell type
such help is antigen specific. We also consider

during the acute, chronic, and memory phases
whether help is delivered early or late in the
of a response.
response and examine the events occurring
Over the past several decades, a substan-
within lymphoid tissues that allow effective
tial literature has dealt with these various as-
communication between rare antigen-specific
pects of cell-mediated immunity. The key role
cells in the two T cell lineages. We end with
of major histocompatibility complex (MHC)
some speculations about the roles of the many
class I molecules in presenting short pep-
distinct mediators that have been reported to
tide antigens to the clonal receptors of CD8+
determine the nature and magnitude of CD8+
T cells (TCRs) has been amply documented
T cell responses and the possibility that how
and the cell biology of antigen processing
cellular cooperation is orchestrated for these
that leads to formation of these peptide-MHC
responses might represent a general strat-
ligands well delineated (9–11). In more re-
egy for cell-cell interactions in the immune
cent years, there has been a renewed inter-
system.
est in better understanding the contributions
of other cell types to the proliferation, ef-
fector function, and memory cell behavior of
the CD8+ T cell subset. A growing apprecia- WHY CD4+ T CELL HELP?
tion of the impact of innate signals arising in CELL-CELL INTERACTIONS AS
response to both pathogen-derived and host CHECKPOINTS IN LIMITING
stress response stimuli (12–14) has led to a AUTOIMMUNITY
reexamination of the early events in the ac- The goal of the immune system is to protect
tivation of CD8+ T cells and in their devel- the organism from foreign infectious agents
opment of effector function. Intimately con- while avoiding pathology during such useful
nected with this issue is the role of dendritic responses or owing to undesirable reactivity
cells (DCs), not merely in presenting antigen, to self (18). This goal is achieved via multi-
but in supplying critical costimulatory and ple checkpoints operating on both precursor
differentiation-inducing mediators that guide lymphocytes during their development in pri-
the developing lymphocyte response (15, 16). mary lymphoid tissues (central tolerance) and
In addition, there has been increasing atten- on mature cells in secondary lymphoid tis-
tion to the role of CD4+ T cells in CD8+ sues as well as parenchymal sites (peripheral
T cell responses (5, 17), driven in part by a de- tolerance) (19, 20).
520 Castellino · Germain

In the early 1970s, investigators first pro- lymphocytes to interact, either directly with
posed that B cell activation requires two sig- each other or through the intermediation of
nals: one provided by the recognition of the DCs, further reduces the risk of inappropri-
antigen and the other by the interaction with ate responses to nonthreatening antigens, be-
helper cells recognizing the same or a phys- cause inadequate activation/maturation of any
ically linked antigen. Failure to receive the of the cooperating cell types limits the clonal
second signal was postulated to induce B cell expansion and/or effector capacity of poten-
tolerance and therefore to limit reactivity to tially auto-aggressive cells in the other sub-
self in light of somatic hypermutation. This sets. A lack of CD4+ T cell help in particular
two-signal model was based on the presump- clearly does not prevent initiation of poten-
tion that B cells whose immunoglobulin re- tially pathologic responses by other cell types;
ceptors gained self-reactivity by the mutation rather, the absence of such help controls the
process would require, for their full activation, duration of such responses, limiting the dam-
a second signal from activated self-reactive age to the host. As detailed below, a lack of
CD4+ T cells that should have been deleted or CD4+ T cell help will allow an acute but not
inactivated as a result of thymic and periph- a sustained or memory CD8+ T cell response.
eral tolerance mechanisms (21). Since then, Similarly, in the absence of CD4+ T cell help,
several observations have validated the core B cell responses can be initiated, but the so-
conceptual (although not the specific mecha- matic hypermutation, isotype switching, and
nistic) features of this model both for B cells clonal selection necessary for production of
and CD8+ T cells (22–26). high-affinity immunoglobulins is restricted
With respect to T cells, many of the im- (32, 33). Such observations provide support
mature cells that exhibit high affinity for self- for the thesis that a major reason for evolv-
peptides presented in the thymus are deleted ing an immune system with critical require-
there, but such negative selection is not a fool- ments for cell-cell cooperation is to impose
proof mechanism, and some T cells capable controls on the development of inappropri-
of damaging autoimmune reactivity escape ate responses, as originally postulated in the
to the periphery (27). To further limit effec- two-signal model (21).
tor responses to both self as well as harmless
environmental antigens, several mechanisms
regulate lymphocyte activation in the periph- ROLE OF CD4+ T CELL HELP IN
ery. The dose and affinity of the antigen THE GENERATION OF ACUTE
required to activate mature T lymphocytes EFFECTOR VERSUS MEMORY
is higher than for immature thymocytes (28– CD8+ T CELL RESPONSES
30), thus facilitating activation-related ig- If the involvement of CD4+ T cells in
norance of many self-peptides presented in CD8+ T cell responses is to provide a check
the periphery. In addition, T cell responses on unwanted, possibly tissue-damaging re-
are regulated by requirements for concurrent actions, at what point in the development
or sequentially ordered signaling. Prior to of such responses does this regulation take
their interaction with naive T cells, antigen- place? In addressing this question, it is use-
presenting cells (APCs), in particular DCs, ful to summarize the prototypic course of
require stimulation through innate receptors, CD8+ lymphocyte responses as they are cur-
such as Toll-like receptors (TLRs), to acquire rently understood from studies using vari-
the capacity for highly effective triggering of a ous acute infection models in mice (7) and,
T cell and for the production of mediators that to a more limited extent, from the analy-
augment T cell clonal expansion, viability, sis of infected humans (34). Naive CD8+
and development of effector capacity (12, 31). T cells are long-lived resting cells that mi-
A requirement for multiple antigen-specific grate continuously from the blood to the
www.annualreviews.org • CD 4+ and CD8+ T Cell Cooperation 521

secondary lymphoid tissues and survive with of the initial burst size) (43, 44), suggest-
only limited division via the recognition of ing that loss during the contraction phase
MHC–self-peptide ligands and exposure to is not a passive default pathway owing to
what are called homeostatic cytokines, of the intrinsic short life of activated T cells,
which IL-7 is the most important (35–38). but rather a tightly regulated process in-
Exposure of a naive host to an infectious volving several death-inducing mechanisms
agent, especially a rapidly replicating virus, and the selective sparing of certain activated
evokes a cell-mediated response with three lymphocytes.
distinct phases: activation/expansion, con- The field’s view of where CD4+ T cells
traction, and maintenance/memory (4). The participate in this sequence of events has
activation/expansion phase typically peaks changed over time. Early in vivo experiments
one to two weeks after infection begins and involving allograft rejection and in vitro stud-
is characterized by the exponential prolifer- ies of allogeneic mixed lymphocyte reactions
ation of antigen-specific T cells. Once the concluded that MHC class II–specific CD4+
T cells are fully activated, they leave the lymph T cells were necessary for the generation of
nodes and accumulate in the peripheral tis- cytotoxic CD8+ T cell responses and led to
sues, where they come in direct contact with the original concept of CD4+ T cell “help”
infected parenchymal cells and exert their ef- (TH) as essential for the clonal expansion of
fector functions. Pathogen numbers increase naive CD8+ T cells (1, 26, 45–50). On the
dramatically during the early part of this first basis of studies first conducted more than
phase, then decline prior to the peak of CD8+ two decades ago (51–53) and confirmed by
T cell expansion, as a cumulative result of more recent experiments (54), investigators
innate defenses and the antigen-specific ac- believed that the processed antigens seen by
tivity of the expanding CD8+ effector popu- CD4+ T cells and CD8+ T cells involved in
lation. A week to ten days after the initiation such cooperative responses must reside on the
of the immune response, a contraction period membrane of a single APC for effective deliv-
begins. This is characterized by the apopto- ery of TH. Evidence that neutralization of IL-
sis of more than 90% of the activated T cells, 2 or blockade of the IL-2 receptor in culture
massive cell death that is required to maintain severely limited cytotoxic CD8+ T cell re-
quasi-constant numbers of T cells throughout sponses (55–59), and data showing that CD4+
the life of the individual. T cells were a major source of IL-2 (60), all
If the response was effective in clearing were consistent with TH function being de-
the infection, and in an intact host with all pendent on the local paracrine delivery of this
other aspects of the immune system acting in cytokine. This concept of TH function led to
a physiological fashion, this death phase will a simple hypothesis: CD4+ and CD8+ T cells
spare a small number of T cells that are main- have to be stimulated by antigen on the same
tained over time through limited divisions in APC so that IL-2 secreted by the CD4+ T cell
response to cytokines, particularly IL-15 (39, can act on a neighboring CD8+ T cell ex-
40). This small pool of memory cells is be- pressing high-affinity IL-2 receptors. This cy-
lieved by most, but not all, investigators to be tokine secretion-signaling link was presumed
crucial in protecting the individual upon re- to play a key role in vivo in controlling the
infection with the same or a related organism early phase of expansion of the small number
because its members are capable of more rapid of naive CD8+ precursors reactive with the
and potent effector responses and because antigens of an infectious organism or minor
these cells possess the ability to migrate and H antigens.
patrol peripheral tissues (4, 41, 42). The pro- Since then, several findings have chal-
portion of CD8+ T cells that survive as mem- lenged this original model of CD4+ -CD8+
ory cells is remarkably constant (5%–10% T cell cooperation. The observation that both

DCs and CD8+ T cells can transiently secrete tent infection when higher doses of the same
IL-2 upon activation (61–65) raised questions agent were used. In the latter animals, re-
about the role of activated CD4+ T cells as sponses were impaired owing both to the dele-
unique producers of this cytokine and of IL- tion of some virus-specific CD8+ clones and
2 as the key mediator of TH. The picture to the persistence of CD8+ T cells without
became more complex when several studies effector functions, and the exhaustion of the
showed that CD4+ T cells were dispensable CD8+ T cell response was more pronounced
in the clearance of acute viral infections, argu- in the absence of CD4+ T cells (73–75,
ing against an absolute dependence of CD8+ 78).
T cells on TH for development of a clonally Although these studies first documented
expanded effector population (66). This find- a critical role for CD4+ T cells in sustain-
ing led to the hypothesis that TH was essential ing rather than initiating CD8+ effector re-
for immunity to antigens such as tissue grafts sponses, they did not reveal whether the
that lacked molecular stimuli for cells of the CD4+ subset contributed directly to the sur-
innate immune system [adjuvants, or PAMPs vival of activated CD8+ T cells or indirectly,
(pathogen-associated molecular patterns) in for example, because of the inability of CD4+
Janeway’s terminology (67)], but that help was T cell–deficient animals to mount a strong
not required for responses to antigens asso- B cell response that in turn could lead to per-
ciated with potent sources of these stimuli, sistence of antigen and inflammation, both of
such as live viruses and bacteria. In this model, which have detrimental effects on the survival
TH was required to activate quiescent APCs of functional cytotoxic CD8+ T cells (84, 85).
(DCs), a functionality that was provided in the Newer methods, such as tetramer tracking of
case of infectious agents by ligands for TLRs, specific T cells and/or the use of TCR trans-
such as dsRNA (TLR3), lipopolysaccha- genic clonal T cell populations, have allowed
ride (TLR4), and CpG-containing oligonu- resolution of this issue. A series of recent
cleotides (TLR9) along with their induced studies have all reached a similar conclusion,
products, such as type 1 interferons (68, 69). In namely that in both classical TH-dependent
the absence of such signals, CD40L (CD154) and TH-independent immunization models,
expression by antigen-activated CD4+ T cells CD4+ T cells are very often dispensable for
appeared to be responsible for promoting a early clonal expansion and the generation of
similar activation of APCs through interac- primary CD8+ cytotoxic effectors (although
tion with CD40 expressed on these latter cells they may augment both aspects of the CD8+
(54, 70–72). T cell response to a greater or lesser degree),
Doubts about this new formulation arose but are required for the generation of an opti-
with the publication of new studies of antivi- mal pool of functional memory CD8+ T cells
ral responses after the acute phase. In both (80–83).
chronic infections and recall (memory) re-
sponses, a dependence on CD4+ T cells was
noted that was at odds with the lack of such WHEN IS TH REQUIRED FOR
a requirement for acute CD8+ effector re- MEMORY CELL
sponses to the same agents (73–83). The ap- DEVELOPMENT?
parent correspondence between the absence If the preponderance of evidence is now that
of strong inflammation and a need for CD4+ TH has its primary role in the formation of
T cell help was lost. Such studies showed a useful memory cell pool [some evidence
that depletion of CD4+ T cells did not af- to the contrary notwithstanding (50)], when
fect pathogen clearance mediated by CD8+ does this contribution occur during the sev-
T cells, if mice were acutely infected with eral phases of the CD8+ T cell response? Pro-
low numbers of organisms, but led to persis- liferation of antigen-specific CD8+ T cells

begins within 24–30 h of antigen introduc- In at least one model involving bland
tion in vivo (86). The activated CD8+ T cells priming with tumor cells, the helpless CD8+
then typically undergo more than 7–8 cell di- T cells showed a defect in clonal expan-
visions in a process that appears to be indepen- sion upon antigen reexposure in vitro (81).
dent of further foreign antigen recognition by A follow-up study has provided evidence
the TCR of these CD8+ T cells (87, 88), al- that this proliferative defect is the result of
though a role for self-MHC recognition in TRAIL production by the helpless CD8+
driving this expansion has not been ruled out. T cells, which leads to their death by apop-
If the CD8+ T cells operate on autopilot dur- tosis shortly after antigen stimulation (89).
ing this proliferative phase, could TH acting Although these recent data can explain the
at this very early point possibly have an ef- lack of vigorous secondary responses or sus-
fect on memory cell survival weeks or months tained memory cell activity upon tumor or
later? Some might consider it more sensible infectious challenge, they do not account for
that TH acts when the expanded CD8+ T cells the smaller number of antigen-specific mem-
start to undergo rapid attrition, or even very ory CD8+ T cells in the maintenance phase,
late, in what would be called the maintenance when priming occurs in the absence of CD4+
phase. As is typical in immunology, different T cells. Nor do these data account for the
studies have claimed to provide evidence for more limited ability of those cells that re-
all three possibilities. main several weeks after priming in the ab-
Support for an early effect of TH on sence of CD4+ T cells to show acute cytokine
long-term memory CD8+ T cell survival and responses within hours after restimulation
function came from experiments in which (80–83), before TRAIL-induced death could
CD4+ T cells were removed from the prim- affect the outcome. These considerations sug-
ing environment, or antigen-activated CD8+ gest that the TRAIL limitation of secondary
T cells were removed from the CD4+ T cell– expansion is just one of a number of defects
containing host within a few days of initial imposed on the CD8+ T cells by an early lack
antigen exposure. CD4+ T cell depletion later of TH.
than three days after antigen injection in any The opposite conclusion about the time
of several model systems produced a memory when TH affects the memory pool was
CD8+ T cell pool whose size and functional- reached by different investigators. In a study
ity was the same as in animals with an intact using viral or bacterial antigen delivery, the
CD4+ T cell cohort (81–83). Furthermore, absence of a polyclonal CD4+ T cell popula-
such helped CD8+ T cells, if transferred into tion in the host led to a late, gradual decline
a CD4+ T cell–deficient recipient, survived, in the number of memory CD8+ cells even
developed into functional memory cells, and when priming occurred in the presence of
protected the host from a subsequent chal- antigen-specific TH (90). These investigators
lenge with the same infectious agent used concluded that antigen-specific CD4+ T cell
for the priming. The conclusion drawn from activation was not required at priming to pro-
these studies was that once CD8+ T cells have gram a small population of CD8+ T cells to
been primed in the presence of CD4+ T cells, develop into memory cells, but rather that an
the latter are no longer required for the even- antigen-unspecific bystander effect, probably
tual emergence of useful memory cells many mediated by cytokines, operated late in the re-
weeks later. Because these studies analyzed sponse to maintain the viability of the CD8+
only the acute secondary response, it remains memory pool (90). A key point is that in this
unclear whether CD4+ T cells are also re- study the conclusion that antigen-specific TH
quired at the time of boosting for the second was not necessary at priming for the genera-
wave of effectors to survive and develop into tion of a maximal pool of functional mem-
a memory population as well. ory CD8+ T cells relied exclusively on the

detection of similar numbers of activated IL- activation of CD4+ T cells, that is, by TH (F.
7Rαhi CD8+ T cells in wild-type and CD4+ Castellino, manuscript submitted). Together,
T cell–deficient animals at the peak of the pri- these various observations indicate that it may
mary response (90). Kaech et al. had previ- have been misleading to assume, on the basis
ously proposed that high surface expression of a failure to observe an increment in IL-
of IL-7Rα on CD8+ T cells during the early 7Rαhi cells, that no programming for memory
primary response could be used to identify cell development occurred in the presence
the prememory CD8+ T cell pool, a sub- of TH. We wish to stress, however, that be-
population of activated T cells that preferen- yond the contribution of early TH-dependent
tially gave rise to long-lived memory cells (91, programming of CD8+ T cells to long-term
92). The principle evidence that cells of this memory, an additional role for bystander
phenotype were programmed for survival as polyclonal CD4+ T cells in the maintenance
memory cells involved their twofold decline of committed memory CD8+ T cells is not
in number during the contraction phase of the ruled out by available data.
response, compared with a more than 20-fold
decline for IL-7Rαlo cells, as well their per-
WHERE IS TH DELIVERED
sistence after adoptive transfer into naive ani-

mals, compared with the nearly complete loss EARLY AFTER PRIMING? PART 1
of IL-7Rαlo cells under the same conditions The “when” of TH delivery now seems rea-
(91). sonably well answered, with the bulk of ev-
However, although the correlation be- idence in favor of an early programming ef-
tween IL-7Rα expression and survival was nu- fect of TH on CD8+ T cells that enhances
merically robust in this one study, in other the ability of at least a fraction of the re-
experimental situations this was not the case. sponding population to survive as long-term
Under a variety of priming conditions involv- memory cells and to show heightened effector
ing either live agents or nonreplicating vac- function upon recall stimulation (93). Thus,
cine formulations, from 30% to 70% of the CD4+ T cells must deliver one or more sig-
activated, dividing CD8+ T cells at the peak nals to the CD8+ T cells directly or indirectly
of the response have the IL-7Rαhi pheno- at the time of, or shortly after, initial contact
type, yet only ∼5% of the cells remain several with antigen-bearing APCs. This leaves the
weeks later (90, 92; F. Castellino, manuscript “where” and “how” to be addressed. Given
submitted). Thus, although a high level of that in a normal naive repertoire, the fre-
this cytokine receptor is a necessary condi- quency of CD4+ and CD8+ T cells specific for
tion for long-term survival of an activated antigens from a single infectious organism is
CD8+ T cell, it is not a sufficient condi- quite low, a mechanism for bringing these rare
tion. Furthermore, we have confirmed that cells together in time and/or space is required.
the frequency of CD8+ T cells marked by The obvious platform for such signal transfer
high IL-7Rα levels does not differ early af- is the APC, and indeed, a substantial literature
ter priming in the presence or absence of TH indicates that both the MHC class II–bound
(F. Castellino, manuscript submitted). How- ligand that stimulates the CD4+ T cells re-
ever, we can detect an enhanced frequency of sponsible for TH and the MHC class I–bound
a phenotypically distinct subpopulation of IL- ligand involved in activating the CD8+ T cells
7Rαhi -activated CD8+ T cells arising early af- must be on the same APC membrane for co-
ter priming in the presence of TH, as com- operation to be effective (51, 54). The ques-
pared with the same priming conditions in tion that has preoccupied the field for some
the absence of TH. The number of these time involves temporal details of such coop-
cells corresponds precisely to the increment in eration: whether the CD4+ and CD8+ T cells
long-term memory cells provided by antigen- must simultaneously engage the same APC

(the three-cell cluster model) or if the antigen- in vitro (54). The in vivo data are less clear,
activated CD4+ T cell can leave its mark by li- although some experiments appear consistent
censing the DC for delivery of help to a CD8+ with the licensing concept (54, 70–72, 97).
T cell after the CD4+ T cell has left the scene However, this model has several conceptual
(94). The three-cell cluster model is consis- limits, and a number of assumptions were
tent with the early hypothesis that CD4+ and made when it was proposed: that CD4+ T cell
CD8+ T cells need to recognize their specific binding to antigen-bearing DCs is short-
antigens simultaneously on the same APC, so lived; that naive T cells cannot sense each
that local paracrine action of cytokines such as other’s presence; and that in lymph nodes,
IL-2 secreted by an APC-bound CD4+ T cell naive T cells randomly scan APCs. Regard-
can support clonal expansion by the colocal- ing this last point, one key argument made
ized CD8+ T cell (46). A recent variation of for CD4+ T cells moving around rapidly and
this paracrine three-cell cluster model sug- licensing many DCs was to prevent toleriza-
gests that antigen-primed CD4+ T cells can tion of CD8+ T cells upon engagement of
directly stimulate CD8+ T cells via CD40L cognate antigen on a nonlicensed DC (68).
when the two lymphocytes are in close prox- But if there is no specific mechanism that at-
imity on an APC (80). Here, again, there is tracts CD8+ T cells to the licensed DC, it is
controversy, because other investigators find still highly likely that a CD8+ T cell would
no critical role for CD40 expression by CD8+ find an antigen-bearing, unlicensed DC be-
T cells in primary or memory responses (95, fore that CD8+ T cell has a chance to en-
96). gage a DC that had already engaged a CD4+
In the minds of many immunologists, the T cell. Given the few specific CD8+ T cells in
strongest argument against the three-cluster a naive repertoire (98), this tolerance induc-
model is the low probability that three rare tion would be a potentially devastating blow to
cells (an antigen-bearing DC coming from an the development of a useful immune response.
infected site, an antigen-specific CD4+ T cell, One way around this limitation is to postu-
and an antigen-specific CD8+ T cell) will late that there is a period of time after antigen
find each other in the same place at the same recognition involving an unlicensed DC dur-
time (26, 54). The intuitive feeling that such ing which delivery of the proper signal can
clusters could not be efficiently generated led rescue a CD8+ T cell from inactivation. This
to a new model in which antigen-stimulated period would allow the CD8+ T cell much
CD4+ cells activate DCs via CD40L-CD40 more time to find a DC that had at some point
interaction, and the resultant “licensed DCs” interacted with a CD4+ T cell, but it would
become fully competent to activate naive also remove one of the main arguments in sup-
CD8+ T cells, even in the absence of an asso- port of the licensing model. Second, the as-
ciated CD4+ T cell (54, 70–72). In one ver- sumption that the rare nature of specific lym-
sion of this model, the CD4+ T cell then phocytes would limit CD4+ and CD8+ T cell
moves from DC to DC, anointing each with coengagement of a single DC is based on the
the capacity to provide help to a CD8+ T cell idea that the length of time a T cell spends on
that subsequently binds to one of these APCs, an APC is short relative to the time it takes a
which also bears the appropriate peptide- T cell to find that APC. But studies 30 years
MHC class I ligand. This flitting around was ago with guinea pig cells showed that antigen-
proposed to amplify TH function by creating specific CD4+ T cells could stay associated
many licensed DCs for each antigen-activated with APCs bearing specific antigen for at least
CD4+ T cell. several hours (99). This may be more than
There is clear evidence for an enhanced ca- enough time for a specific CD8+ T cell to ar-
pacity of DCs preexposed to activated CD4+ rive, given that such cells complete a passage
T cells to support CD8+ T cell responses through a lymph node in about the same time

span (100). Third, and most important, the involved a combination of antigen-activated
model assumes that cell-cell interactions are CD4+ T cells and naive CD8+ T cells,
completely random; if the antigen-dependent which is the situation relevant to the delivery
interaction of a CD4+ T cell and a DC gener- of TH.
ates a signal that attracts naive CD8+ T cells, Returning to the issue of how long a CD4+
then the likelihood of a useful three-cell clus- T cell remains on an antigen-bearing DC,
ter arising increases greatly. there is a reasonable consensus that follow-
New data relevant to these issues has re- ing an early phase in the first few hours
cently become available from imaging studies after antigen introduction during which tran-
of lymphocyte-DC interactions within intact sient CD4+ -DC interactions occur (101), a
lymph nodes. In terms of cell movement, sev- period of long-lived association of the two
eral groups have conducted detailed analyses cell types ensues that can last for many hours
of the rate and directionality of migration for (101, 105). Given the lack of evidence for
both CD4+ and CD8+ T cells in lymph nodes cytokine gene expression by CD4+ T cells
in the absence and presence of specific anti- during the early transient interaction stage,
gen and/or inflammatory stimuli (86, 101– it is unlikely that extensive DC licensing oc-
104). Each of these studies concluded that curs during this period. During the second
naive T cells move at an average speed of phase (between 6 h and 30 h following anti-
∼8–12 μm/min in a manner that is consistent gen introduction), most specific CD4+ T cells
with a random walk, that is, with unguided do not make contacts with multiple DCs but
movements not directed toward a particular rather show monogamous interactions (101,
location. The principle analytic method used 105, 106). During this time span, initiation
to draw this conclusion is a plot of displace- of the CD8+ proliferative phase begins, so it
ment versus time1/2 . A straight-line relation- does not seem likely that the flitting hypoth-
ship in such a plot is well recognized in chem- esis in which a single CD4+ T cells licenses
ical physics to be consistent with a random many DCs early on fits the data. Except for
walk, like gas molecules diffusing by Brown- a model in which rescue of function among
ian motion. The studies of Cahalan and col- CD8+ T cells initiating their response on un-
leagues (101, 102) are the most extensive in licensed DCs is the predominant mode for
this regard and involve both steady state and delivery of TH, one is left with two possibil-
immunogenic conditions. They found no evi- ities: (a) that random interaction among the
dence that CD4+ T cells showed any deviation relevant cells is the underlying mechanism,
in their paths of travel near activated DCs, with all the problems this hypothesis poses
from which they concluded that contact be- for avoiding tolerance and ensuring an effi-
tween these cell types was dictated by two un- cient response at low precursor frequency; or
guided search strategies, one the rapid move- (b) that guided interactions occur under con-
ment of the dendrites of the DC and the other ditions not analyzed in these existing studies
the random migration of the CD4+ T cells in of CD4+ or CD8+ T cells alone. Our very re-
the T cell zone of the lymph node (101, 102). cent experiments suggest that the latter is the
In the case of CD8+ T cells studied without correct answer.
CD4+ T cell activation, two studies saw no
influence of activated but nonantigen-bearing
DCs on the behavior of the naive lymphocytes WHERE IS TH DELIVERED
(103, 104), whereas a third saw some deviation EARLY AFTER PRIMING? PART 2
from the expected straight-line random walk To understand how the immune system could
plot with activated DCs present, but only for a organize itself to promote interactions effec-
subset of the T cells and with no clear mech- tively among rare cells, a summary of the
anism (86). However, none of these studies dynamics of antigen, DC, and inflammatory

mediator trafficking to draining lymph nodes During the period in which this delivery
and of the process of lymphocyte recircu- of free antigen, DC-associated antigen, and
lation is helpful. Antigens injected subcuta- inflammatory signals is occurring, T cells in
neously reach a draining lymph node in two the naive and central memory recirculating
temporally distinct waves. Soluble molecules pool are entering and trafficking through the
directly drain via the afferent lymph together lymph node. These T cells express CCR7
with tissue-produced inflammatory cytokines and CD62L; the interactions of CCR7 with
such as TNF. This trafficking via lymphat- CCL21, which has been produced by stro-
ics allows antigens and cytokines to reach the mal elements and decorates high endothe-
lymph nodes within minutes, where they en- lial venules (HEV), and of CD62L with its
ter the conduit network that is the distri- carbohydrate ligand peripheral lymph node
bution system for lymph within the lymph addressin, which is highly expressed on the
node proper (107, 108) and are taken up luminal surface of these endothelial cells,
by subcapsular macrophages and by conduit- lead to rolling, integrin activation, and trans-
associated, resident DCs, to be processed and endothelial migration of the T cells into the
presented by these cells within hours (109– lymph node (42, 100, 121–123). HEV are con-
111). A second wave of presentation relies centrated in the interfollicular region (IFR) of
on tissue-resident DCs that acquire the anti- noninflamed lymph nodes, between primary
gen in the periphery (109, 112). Local in- B cell follicles and at what many investiga-
flammation induces rapid modifications in tors consider the outer rim of the T cell zone
the pattern of expression of chemokine re- (124). These specialized vessels also occur in
ceptors that regulate the migration of DCs certain areas of the paracortex (125). HEV are
toward and their positioning within lymph closely associated with the conduit network
nodes (113–117). Immature DCs located in through which antigens and cytokines reach
peripheral tissues express receptors (CCR1, the lymph node interior, and the IFR is the
CCR2, CCR5, CCR6, CXCR1) for inflam- zone through which tissue-resident DCs traf-
matory chemokines (CCL3, CCL4, CCL5, fic on their way to the deeper paracortical re-
CCL20). This pattern of expression allows gion (107, 108, 124). Thus, recirculating naive
DCs or their blood precursors to be attracted and central memory T cells first have access to
to inflammatory sites, where they internal- antigen-bearing DCs immediately upon exit
ize antigens and receive maturation stimuli. from the HEV, where they encounter a dense
These stimuli (e.g., TNF-α) induce the DCs meshwork of resident DCs that have sampled
to decrease expression of the receptors for antigen from the conduit flow and have poten-
inflammatory chemokines and to upregulate tially been activated by PAMPs and inflam-
the chemokine receptor CCR7, making them matory cytokines in this same fluid. Indeed,
responsive to CCL21 (SLC) present on the static sequential imaging studies have shown
lymphatic endothelium (100, 115, 118, 119). that T cells first bind stably to antigen-bearing
This in turn promotes DC migration via the DCs in this IFR, rather than more gener-
lymphatics into the subcapsular space of the ally throughout the paracortical T zone (110,
lymph node and from there into the lymph 124).
node parenchyma along pathways between How do naive CD8+ T cells find the right
the B cell follicles, from which they eventu- APC? Encounters between naive T cells and
ally enter the paracortical T cell zone with DCs have been postulated to depend on their
their antigen cargo. Imaging studies suggest common attraction to CCL19 and CCL21
that these newly arriving DCs integrate them- (126). Such an attraction would bring both
selves into a large complex network of resident DCs and T cells to the same area of the lymph
DCs, where they then are available to interact node, but it would not necessarily favor the
with T cells (120). attraction of naive CD8+ T cells to licensed

DCs or DC-CD4+ T cell clusters. Such con- partments, some combination of chemokine-
siderations bring the discussion back to the sis and chemoattraction was the most log-
critical issue of discriminating between ran- ical explanation for the focusing of naive
dom and focused interactions within lymph CD8+ T cells on DCs engaged in produc-
nodes. tive interactions with CD4+ T cells. Using a
One limitation of the existing analyses of blocking antibody strategy, we looked for a
lymphocyte movement is that observing a lin- chemokine whose neutralization would elim-
ear relationship between cell displacement inate the CD4+ T cell–dependent accumu-
and time1/2 is a necessary but not sufficient lation and DC interaction behavior we had
condition for establishing random walk be- observed. The results of this screen were un-
havior. Especially if short-range chemoattrac- expected. CCL3 and CCL4 (MIP1β/α), two
tion is present, this analysis can be mislead- well-known inflammatory chemokines, were
ing (127, 128). Mempel et al. (86) dealt with responsible for focusing naive CD8+ T cells
this limitation by examining the local turning on licensed DCs and/or antigen-dependent
angle of CD8+ T cells as they encountered CD4+ T cell–DC clusters. Neither of these
DCs, finding little evidence for a significant chemokines had been reported as playing a
deviation of naive cells toward the preacti- role in the initiation of T cell responses. The
vated, antigen-bearing DCs used in this study. cognate receptor, CCR5, was believed to be
However, these experiments did not include upregulated only after TCR engagement with
antigen-activated CD4+ T cells capable of de- antigen as part of a differentiation process
livering TH. This left open the possibility that that produced effector cells with a capacity
in the presence of a suitable antigen-driven to home to peripheral sites of inflammation
interaction between CD4+ T cells and DCs (129). This seemingly paradoxical result was
there would be a directed attraction of CD8+ explained by our observation that (a) a sub-
T cells to the site of this preexisting productive stantial subpopulation of naive CD8+ T cells
cell-cell contact. Given the discussion above, in the lymph node draining site of inflamma-
just such a mechanism in which CD8+ T cells tion expresses CCR5 prior to cognate antigen
are attracted selectively to DCs that have been recognition; and (b) these cells are sensitive to
or are being licensed by CD4+ T cells would attraction by CCL3 and CCL4 (F. Castellino,
make the most physiological sense. manuscript submitted).
Based on these considerations, we have re- The anatomy of the lymph node is quite
cently analyzed whether antigen-dependent consistent with these findings. The conduits
interactions of CD4+ T cells with DCs af- that bring inflammatory signals from a pe-
fects the migratory properties of naive CD8+ ripheral infected site open onto the cells that
T cells within lymph nodes. Our studies invest HEV and through which naive CD8+
showed that CD8+ T cells preferentially ac- T cells enter the lymph node parenchyma
cumulated in an antigen-independent man- (100, 107, 108). Thus, as they make their
ner in lymph nodes in which CD4+ T cells way into the lymph node and engage the
were undergoing antigen-specific activation. dense array of antigen-bearing DCs that sur-
Intravital 2-photon imaging documented that round the HEV, naive CD8+ T cells would
naive T cells interacted three- to fourfold be exposed to a high concentration of the
more often with DCs that bore antigenic com- mediators that we have found can induce
plexes recognized by available CD4+ T cells CCR5 upregulation, thus preparing these
than with neighboring DCs that lacked such cells for enhanced rates of interaction with
antigen but were equivalent in activation the subset of DCs bearing foreign antigen and
state (F. Castellino, manuscript submitted). interacting with the CD4+ T cells respon-
Because chemokines are the key molecules sible for TH function. Blocking CCL3/4-
guiding cell movement in lymphoid com- mediated focusing of CD8+ T cells on DCs

that interact with antigen-activated CD4+ under immunogenic conditions, interactions

T cells leads to the elimination of mea- between the few relevant cells are optimized
surable effects of TH on the long-term by chemokine guidance mechanisms. In the
development of memory in a nonreplicat- case of CD8+ T cells, both inflammation and
ing vaccine model (F. Castellino, manuscript antigen-specific activation of CD4+ T cell are
submitted), illustrating the crucial role of di- required for such a focusing pathway to op-
rected migration in this aspect of CD8+ T cell erate. This allows the immune system to ef-
immunity under at least certain immuniza- ficiently activate CD8+ T cells even though
tion conditions. The absence of any known their frequency is low in the naive repertoire,
gross defect in antiviral immunity in humans while maintaining the cell-cell cooperation
with CCR5 deficiency (130, 131) raises the checkpoints required the keep these poten-
interesting question of whether these find- tially damaging effector responses under strict
ings on cell recruitment are restricted to the control.
mouse or to certain conditions of immune

activation.
Our experiments did not resolve the issue THE HOW: SIGNALS INVOLVED
IN DELIVERY OF TH
of whether the generation of a three-cell clus-

ter, the licensing of the DCs, or both are re- The two-signal hypothesis discussed at the be-
quired for functional delivery of help. We did ginning of this review was originally based on
find that CCL3 and CCL4 are secreted by the activity of two cell types, but it has mor-
DCs in response to TLR signaling and that phed over the years to “two signaling events
this secretion is synergistically increased by by distinct receptor types” involving a single
CD40 ligation. We also found abundant se- cell (134). More recently, this simple view has
cretion of the above chemokines by TCR- grown much more complex, with a large ar-
stimulated naive CD4+ and CD8+ T cells ray of simultaneously and sequentially deliv-
(F. Castellino, manuscript submitted). Such ered stimuli recognized to have key roles in
a pattern suggests that the DCs that receive guiding T cell clonal expansion, effector dif-
a TLR signal and then engage in a produc- ferentiation, survival, homing propensity, and
tive interaction with CD4+ T cells would be memory cell performance. Antigen together
most attractive to a naive CD8+ T cell that has with a plethora of cell membrane–associated
been exposed to inflammatory signals and that costimulatory molecules (135) as well as se-
has expressed CCR5. Interestingly, CCL3 and creted and cell-associated cytokines (136, 137)
CCL4 are produced in large amounts by contribute to driving a resting T cell into cell
TLR-activated DCs, but their production is division, modulating the balance of pro- and
not sustained (123). Such transient production anti-apoptotic proteins that control cell sur-
by the DCs might have the purpose of requir- vival, and altering chromatin structure to per-
ing the presence of antigen-activated CD4+ mit new gene expression (138, 139). Ligand/
T cells to maintain the chemokine gradient, receptor pairs in the immunoglobulin super-
thus rendering activated DC-CD4+ T cell family [particularly CD28-CD80, CD86 and
clusters rather than licensed DCs alone as the ICOS-ICOS-L (135, 140, 147)], as well as in
most likely to recruit naive CD8+ T cells. The the tumor necrosis factor superfamily [includ-
transient secretion of CCL3/4 by DCs may ing CD40-CD40L, 4–1BB-4–1BBL, CD27-
also have the role of preferentially attracting CD70, CD30-CD30L, and HVEM-LIGHT
naive CD8+ T cells to freshly activated DCs (141)] have all been reported to play criti-
instead of DCs that have been similarly ac- cal and sometimes apparently redundant roles
tivated earlier in the response and that are in CD8+ T cell responses. In addition, there
already exhausted (132, 133). The key mes- is evidence for critical contributions from
sage from these studies is that in lymph nodes, numerous cytokines during acute phases of

CD8+ T cell activation and differentiation whether the be-all and end-all of TH activity
(61, 142, 143) and during later phases of the is promotion of this last step in DC activation,
response, when they regulate the balance be- generating APCs that have an optimal display
tween proliferation and death of activated of all the elements that enhance CD8+ acti-
and memory T cells (40, 144–148). Studies vation, effector differentiation, and memory
in animals with selective defects in expres- cell survival.
sion of individual members of the above lig- A conservative interpretation of these data
and/receptor pairs have shown that none of that we favor is that several different receptor-
them, perhaps with the exception of CD28, ligand combinations with partially overlap-
has an absolutely essential function in the de- ping functions and sequential actions all con-
velopment of CD8+ T cell responses, but tribute to maintaining CD8+ T cell viability
rather each adjusts the balance between prolif- both by synergizing to reach a critical thresh-
eration and death, thus affecting the number old of necessary anti-apoptotic molecules
of T cells that accumulates at the peak of the and/or by sustaining the level of such pro-
response and/or that survives to generate the teins throughout the different phases of the
T cell memory pool. immune response. This concept implies that
This growing body of molecular media- TH does not influence CD8+ T cell memory
tors makes the identification of the specific formation through a single master molecule;
mechanism(s) by which CD4+ T cells affect rather, it produces a population of optimized
CD8+ T cell responses very difficult to un- DCs expressing a host of relevant molecules
ravel. Among all the molecules examined for a and at the same time helps insure that naive
role in TH, CD40 has most consistently been CD8+ T cells interact preferentially with
reported as critical in this process (72, 135). these special APCs.
Maximal expression of CD40 on DCs requires This concept of TH reflecting CD8+
specific activating signals. PAMP stimulation T cell contact with properly signaled DCs
of TLRs is the best-characterized pathway raises an intriguing question. If the initial in-
leading to such upregulation (149, 150), al- teraction of a naive T cell with a licensed ver-
though various forms of mechanical or chem- sus an unlicensed DC were to dictate irrevo-
ical stress (151) or signaling by other recep- cably the ultimate fate of the activated T cell,
tors such as C-type lectins (152) may do the then it would be difficult to explain data show-
same. This increased expression of CD40 in ing that for each antigen specificity in an an-
turn appears to be important for effective tiviral response a similar fraction of the acti-
stimulation of the partially activated DCs by vated cells present at the peak of the response
CD40L expressed on antigen-activated CD4+ survives in the memory pool (153). The diffi-
T cells (149), thus linking innate stimulation culty in reconciling these data arises from the
with antigen-driven responses to produce op- fact that there should be substantial statistical
timally matured and functional DCs. CD40 fluctuations in the fraction of naive precursors
signaling increases MHC display, costimu- of each specificity that find one or the other
latory molecule expression, cytokine secre- type of APC at the beginning of a response be-
tion, and chemokine production, a list that cause of the stochastic nature of events at very
encompasses nearly all the players that am- low precursor numbers. We envision two sce-
plify or sustain CD8+ T cell responses during narios able to reconcile these data with our
either the acute or memory phases. Indeed, model for delivery of TH. The less likely one
in vitro studies are consistent with the notion is that a statistically similar fraction of the
that CD40-stimulated DCs gain the capac- precursors of each specificity finds a licensed
ity to promote CD8+ T cell responses un- DC. The alternative is that there is a window
der conditions in which CD4+ TH is other- of time for antigen-stimulated CD8+ T cell
wise required (54). This raises the question of and/or for their early progeny to be rescued by

receiving help. Such a proposal can be recon- area of draining lymph node. In response to
ciled with our observations if we postulate that inflammation, the DCs increase CD40 ex-
the offspring of individual responding CD8+ pression, becoming more responsive to fur-
T cells are attracted to licensed DCs in the ther stimulation via CD4+ T cells that dis-
same way as naive precursors. This scenario is play CD40L on their membranes because of
not unreasonable considering the strong ev- TCR signaling induced by processed anti-
idence in support of CCR5 upregulation in gen on these innately activated DCs. TLR
response to TCR engagement (129, 131). If stimulation and CD40 ligation also syner-
a subset of each clonally expanded pool made gistically induce the DCs to secrete inflam-
effective contact with licensed DCs, thus ac- matory cytokines and chemokines, including
quiring the capacity to survive during the con- CCL3 and CCL4. Upon entry into a lymph
traction phase of the response and enter the node, antigen-naive CD8+ T cells, which
memory pool, this process would greatly re- through exposure to inflammatory stimuli
duce the impact of stochastic behavior at a low have increased their expression of CCR5, are
initial precursor number and could explain attracted to licensed DCs and/or antigen-
why the residual memory population reflects specific clusters of DCs and CD4+ T cells.
the frequency of the expanded pool at the peak If the recruited naive CD8+ T cells do not
of the response. Imaging studies suggest that find cognate antigen on the DC, their as-
after initial activation on one antigen-bearing sociation will last only a few minutes, after
DC, CD8+ T cells contact many other DCs, which they will leave and engage other DCs
providing at least some evidence consistent in a search for a suitable TCR ligand. If in-
with this proposal (86, 104), but further ex- stead the DC does present the relevant anti-
periments are needed to test its validity. gen, the CD8+ T cell will stop and adhere
for a prolonged time, estimated to be up to
several hours (103). The effect of chemokine
CONCLUSION (CCL3/4) production by the CD4+ T cell–
The analysis of CD4+ -CD8+ T cell interac- DC pair will thus be to enhance the likeli-
tions has followed a long and winding road. hood that rare antigen-specific CD8+ T cells
Although there is still a minority report pend- will find this optimal stimulatory environment
ing, the present day majority view suggests rather than being incompletely stimulated by
that TH is a manifestation of CD4+ T cell– less matured DCs that also bear the cognate
induced differentiation of DCs that in turn ligand. In addition, once the recruited CD8+
optimally supports antigen-activated CD8+ T cell finds its cognate antigen on such an op-
T cell survival during the rigors of exten- timally activated DC, it can also begin to se-
sive clonal expansion and the genetic repro- crete CCL3 and CCL4. The combined secre-
gramming required for effector functional- tion from the CD8+ T cells and the DC will
ity. Our present understanding of the events sustain the chemokine gradient toward these
in this pathway can be summarized as fol- licensed DCs, even if the antigen-stimulated
lows: A combination of microbial products CD4+ T cell has already dissociated. This may
and tissue-derived cytokines act on DCs both recruit more naive CD8+ T cells, but per-
within lymphoid tissues and in the periph- haps plays a predominant role in attracting
ery to induce differentiation events that in- the initial progeny of antigen-activated CD8+
clude the enhanced surface display of MHC T cells, even those first stimulated by nonli-
and costimulatory molecules, the internal- censed DCs, thus preparing a representative
ization and processing of protein antigens, fraction of all CD8+ specificities for entry into
and a switch in the pattern of expression of the memory pool.
chemokine receptors among peripheral DCs This concatenation of events fits well
that enables them to migrate to the T cell with our opening theme of checkpoints for

protection of the host against sustained im- ment of a second lymphocyte subset and to
mune responses that can cause pathology. As provide the full range of signals necessary for
just outlined, a coordinated series of events long-lived responses. This scheme of initial
must transpire in the proper order to pro- innate signaling followed by chemokine-
mote effective memory formation and/or sus- driven coclustering of cooperating lympho-
tain chronic T cells responses, beginning with cytes may be a general solution to the immune
innate stimuli, progressing to an initial pair- system’s needle in a haystack problem, with-
wise interaction of lymphocytes and myeloid out the risk of unwanted autopathological
cells that must be productive to drive recruit- responses.
ACKNOWLEDGMENTS
The authors thank all the members of the Lymphocyte Biology Section, LI, NIAID for helpful
discussion and technical advice during the course of our studies on TH. We are especially
grateful to Alex Huang for his collaboration in the imaging studies in lymph nodes that helped
give rise to some of the concepts developed in this review. We also thank many other colleagues
for discussions about the cellular and molecular mechanisms involved in CD8+ T cell responses
and memory cell generation.
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Contents ARI 7 February 2006 11:41
Annual Review
Contents of Immunology
Volume 24, 2006
Frontispiece
Jack L. Strominger p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p x
The Tortuous Journey of a Biochemist to Immunoland and What He
Found There
Jack L. Strominger p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 1
Osteoimmunology: Interplay Between the Immune System and Bone

Metabolism
Matthew C. Walsh, Nacksung Kim, Yuho Kadono, Jaerang Rho, Soo Young Lee,
Joseph Lorenzo, and Yongwon Choi p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p33
A Molecular Perspective of CTLA-4 Function
Wendy A. Teft, Mark G. Kirchhof, and Joaquín Madrenas p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p65
Transforming Growth Factor-β Regulation of Immune Responses
Ming O. Li, Yisong Y. Wan, Shomyseh Sanjabi, Anna-Karin L. Robertson,
and Richard A. Flavell p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p99
The Eosinophil
Marc E. Rothenberg and Simon P. Hogan p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 147
Human T Cell Responses Against Melanoma
Thierry Boon, Pierre G. Coulie, Benoît J. Van den Eynde,
and Pierre van der Bruggen p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 175
FOXP3: Of Mice and Men
Steven F. Ziegler p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 209
HIV Vaccines
Andrew J. McMichael p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 227
Natural Killer Cell Developmental Pathways: A Question of Balance
James P. Di Santo p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 257
Development of Human Lymphoid Cells
Bianca Blom and Hergen Spits p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 287
Genetic Disorders of Programmed Cell Death in the Immune System
Nicolas Bidère, Helen C. Su, and Michael J. Lenardo p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 321
v
Contents ARI 7 February 2006 11:41
Genetic Analysis of Host Resistance: Toll-Like Receptor Signaling and

Immunity at Large
Bruce Beutler, Zhengfan Jiang, Philippe Georgel, Karine Crozat, Ben Croker,
Sophie Rutschmann, Xin Du, and Kasper Hoebe p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 353
Multiplexed Protein Array Platforms for Analysis of Autoimmune
Diseases
Imelda Balboni, Steven M. Chan, Michael Kattah, Jessica D. Tenenbaum,
Atul J. Butte, and Paul J. Utz p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 391
How TCRs Bind MHCs, Peptides, and Coreceptors
Markus G. Rudolph, Robyn L. Stanfield, and Ian A. Wilson p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 419
B Cell Immunobiology in Disease: Evolving Concepts from the Clinic
Flavius Martin and Andrew C. Chan p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 467

The Evolution of Adaptive Immunity
Zeev Pancer and Max D. Cooper p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 497
Cooperation Between CD4+ and CD8+ T Cells: When, Where,

and How
Flora Castellino and Ronald N. Germain p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 519
Mechanism and Control of V(D)J Recombination at the
Immunoglobulin Heavy Chain Locus
David Jung, Cosmas Giallourakis, Raul Mostoslavsky,
and Frederick W. Alt p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 541
A Central Role for Central Tolerance
Bruno Kyewski and Ludger Klein p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 571
Regulation of Th2 Differentiation and Il4 Locus Accessibility
K. Mark Ansel, Ivana Djuretic, Bogdan Tanasa, and Anjana Rao p p p p p p p p p p p p p p p p p p p p p p p 607
Diverse Functions of IL-2, IL-15, and IL-7 in Lymphoid Homeostasis
Averil Ma, Rima Koka, and Patrick Burkett p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 657
Intestinal and Pulmonary Mucosal T Cells: Local Heroes Fight to
Maintain the Status Quo
Leo Lefrançois and Lynn Puddington p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 681
Determinants of Lymphoid-Myeloid Lineage Diversification
Catherine V. Laiosa, Matthias Stadtfeld, and Thomas Graf p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 705
GP120: Target for Neutralizing HIV-1 Antibodies
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ANRV270-IY24-17 ARI 15 February 2006 1:34

Cooperation Between CD4+

Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland

Annu. Rev. Immunol. Key Words

INTRODUCTION sire to understand better the basis for immune

T cell “help” (TH) has a key impact on CD8+

such help is antigen speciﬁc. We also consider

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sistence after adoptive transfer into naive ani-

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that interact with antigen-activated CD4+ under immunogenic conditions, interactions

mouse or to certain conditions of immune

of whether the generation of a three-cell clus-

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and memory cell generation.

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in the B cell repertoire. Science 248:1373–79

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memory determined by clonal burst size. Nature 369:652–54

www.annualreviews.org • CD 4+ and CD8+ T Cell Cooperation 535

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phocytes. Nature 421:852–56

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coin. N. Engl. J. Med. 343:1020–34

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www.annualreviews.org • CD 4+ and CD8+ T Cell Cooperation 539

133. Langenkamp A, Messi M, Lanzavecchia A, Sallusto F. 2000. Kinetics of dendritic cell

540 Castellino · Germain

Volume 24, 2006

Osteoimmunology: Interplay Between the Immune System and Bone

Genetic Analysis of Host Resistance: Toll-Like Receptor Signaling and

Flavius Martin and Andrew C. Chan p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p p 467

Cooperation Between CD4+ and CD8+ T Cells: When, Where,

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