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Annu. Rev. Immunol. 2000.

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Copyright q 2000 by Annual Reviews. All rights reserved

IMMUNOLOGY AT THE MATERNAL-FETAL


INTERFACE: Lessons for T Cell Tolerance
and Suppression
A. L. Mellor and D. H. Munn

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Program in Molecular Immunology, Institute of Molecular Medicine and Genetics,


Departments of Medicine and Pediatrics, Medical College of Georgia, 1120, 15th St.,
Augusta, Georgia 30912; e-mail: mellor@immag.mcg.edu.

Key Words pregnancy, placenta, macrophages, inflammation, T cells


Abstract Mammalian reproduction poses an immunological paradox because
fetal alloantigens encoded by genes inherited from the father should provoke
responses by maternal T cells leading to fetal loss. Current understanding of T cell
immunobiology and the critical role of inflammatory processes during pregnancy is
reviewed and discussed. Lessons derived from studies on the regulation of T cell
responsiveness during mammalian gestation are considered in the wider context of T
cell tolerance toward some microbial infections and tumors, avoidance of autoimmunity, and tissue allograft rejection.

INTRODUCTIONTHE BIOLOGY OF PREGNANCY


Viviparity is a unique characteristic of mammals. Gestational outcomes avoiding
fetal defects or loss, maternal infection, or morbidity are contingent upon an
intimate association between mother and developing fetus that nurtures the fetus
without provoking maternal immune responses. The process of nurturing new
individuals in this way necessitates exquisite integration and coordination of several complex biological processes, including metabolic, endocrine, vascular, and
immune functions. Almost certainly, ancestral mammals evolved fundamental
mechanism(s) to allow successful viviparity. Rodents and primates possess hemochorial placentas, in which maternal and fetal tissues are not segregated by
basement membranes. Broad similarities in the structure, organization, and development of the maternal-fetal interface are shared by many mammalian species,
but the detailed anatomy and cell biology of the maternal-fetal interface is surprisingly diverse. Most likely, this reflects the need to accommodate variable fetal
masses, numbers of fetus per mother, and different gestational periods as ancestral
mammals evolved. Thus, evolutionary embellishments and diversity between
mammalian species may have obscured fundamental processes necessary for the
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success of viviparity. It is not our intention to review the evolutionary aspects of


viviparity per se. However, we point out that possible evolutionary links between
viviparity in mammalian vertebrates and processes that allow commensal invertebrate life forms to recognize and regulate cellular interactions are the subject
of recent debate (1, 2). In our view, some adaptations were crucial to development
of the placental method of nurturing the young. However, we do not hold that
one critical process allowed mammals to emerge through an evolutionary bottleneck. Most likely, several processes, which evolved for other biological purposes
were exploited and, in time, were adapted to allow mammals to evolve their
unique method of reproduction.
Not surprisingly, attempts to elucidate biological mechanisms that promote
successful outcomes of pregnancy have excited great interest and proved to be a
tremendous challenge; they have also generated a large and complex literature.
We do not address non-immunological aspects of pregnancy in this review except
to illuminate our discussion of selected immunobiological aspects of pregnancy.
From an immunological perspective, placental nurturing of the developing fetus
poses some perplexing questions, the answers to which will help us to understand
other immunological phenomena. Put simply, the questions that exercise most
immunological interest are how the mother provides protection from microbial
infections without mounting a lethal immune response against fetal tissues
expressing paternally inherited alloantigens. In this review we focus on the specific questions of why and how the maternal T cell repertoire tolerates the fetus
throughout gestation. This issue has provoked enormous interest, debate, and
controversy, which testifies to the importance of the issue as well as to the complexity and ignorance that surround the apparent paradox of maternal tolerance
of the fetal allograft. Although this issue has been reviewed extensively, the field
is still active and merits further discussion in view of recent developments that
have appeared in the literature. Unraveling the secrets that resolve the paradox
of fetal tolerance promises to illuminate other important immunological phenomena in which tissues or cells displaying new or foreign antigens are tolerated
despite the potential to eliminate them via host immune responses.

THE IMMUNOBIOLOGY OF PREGNANCY


Excellent reviews on the immunobiology of pregnancy are available, which
address issues such as trophoblast cell biology and anatomy and the role of fetal
antigen presentation, inflammation, uterine macrophages and NK cells, cytokine
production, immunoregulation, tolerance and the innate immune system during
pregnancy (39). The reader is referred to these reviews for detailed discussion
of these and other aspects of pregnancy. While our goal is to review new developments relating to the effect of pregnancy on maternal T cell immunobiology
we will refer to the excellent summations of the field to be found in these reviews
to illustrate the background to our discussion. Space and time limit our ability to

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review this large and developing field. While we have tried to do justice to the
field as it now stands, inevitably we will have omitted some elements that merit
attention. Undoubtedly, these issues will surface in due course if they shed new
light on the complex and perplexing relationship between the maternal immune
system and the developing fetus.
As declared above, our goal is to focus on a specific issue: regulation of maternal T cell responsiveness during gestation. To this end, we address the impact of
pregnancy on maternal T cell responsiveness and, in particular, examine the critical role of inflammation and the innate immune system in this unique immunological situation. While it is necessary to emphasize results obtained from
experimental animal (mostly murine) models of pregnancy, we are aware of the
potential pitfalls of this selective approach. Where possible we refer to evidence
that lessons learned from animal models are relevant to human pregnancy, and
we identify controversies that arise from potential distinctions between mice and
humans. While our selective approach ignores other important aspects of reproductive immunology, we justify this on the grounds that T cells are critical mediators of immunity that lead to clearance of microbial infections, autoimmune
diseases, tissue transplant rejection, and, in some experimental systems, to tumor
regression. Lessons learned from studying how maternal T cell responsiveness is
controlled during pregnancy are likely to illuminate the role of T cell immunoregulation in these important immunological phenomena. Throughout this review
we consider the current status of the paradox of the fetal allograft, which has
been the dominant hypothesis driving research and debate in the reproductive
immunology field for the last four decades (10). However, we also synthesize
older with more contemporary ideas to elaborate a coherent rationale that explains
fetal survival and from which potential lessons for understanding other immunological phenomena involving regulation of T cell responsiveness also emerge.

THE FETUS AS A TISSUE ALLOGRAFT


Genetic Polymorphism and Tissue Alloantigens
From a genetic perspective mother and fetus are never identical in outbred populations because the fetus inherits a different set of polymorphic genes from each
parent. Only in exceptional circumstances, such as experimental matings between
pure inbred animals, are mother and female fetus genetically identical (syngeneic). Strictly, male offspring of syngeneic matings and their mothers are not
completely identical due to Y-chromosome genes encoding tissue antigens such
as the male-specific transplantation antigen H-Y (11). In most mating combinations, multiple tissue antigens differ between fetus and mother and are potential
tissue alloantigens recognizable by T cells. Many genetic polymorphisms are
immunologically inert because they do not change protein-coding sequences. Not
all polymorphisms that change protein-coding sequences are detected by the

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immune system because structural polymorphisms must change peptides bound


to major histocompatibility complex (MHC) molecules to generate tissue alloantigens recognizable by T cells. By recognizing peptides bound to MHC molecules,
T cells can detect extremely low amounts of peptides generated by intracellular
proteolytic degradation of proteins (12). Polymorphisms that alter the rate of gene
transcription can have immunological effects if the density of peptide/MHC complexes is altered as a consequence. In mice, a large number of tissue alloantigens
recognized by T cells, called minor histocompatibility (miH) antigens, have been
characterized structurally (1113). While these are likely to be important fetal
alloantigens, polymorphic MHC genes pose the most significant immunological
barrier to fetal survival because maternal and paternal MHC mismatches are very
frequent in outbred populations and they excite potent T cell responses in tissue
graft recipients. Recent reviews of the role of MHC and miH antigens in tissue
allograft rejections provide detailed assessments of the contribution of antigenic
differences, antigen processing pathways, and T cell subsets to graft rejection (14,
15).

Medawars Paradox and Potential Solutions


According to the laws of tissue transplantation fetal alloantigens encoded by polymorphic genes inherited from the father ought to provoke maternal immune
responses leading to fetal rejection soon after blastocyst implantation in the uterine wall (10, 16). No other tissue, when surgically transplanted between genetically different individuals, enjoys the impunity from lethal host (maternal)
immune responses that characterize the maternal-fetal relationship. This unique
relationship resembles a parasitic condition, albeit a temporary one, in which the
fetus is nurtured and given immunological protection from microbial infections
and potentially lethal maternal immune responses.
Originally, Medawar proposed three broad hypotheses to explain the paradox
of maternal immunological tolerance to her fetus: (a) physical separation of
mother and fetus; (b) antigenic immaturity of the fetus; and (c) immunologic
inertness of the mother (10). The Holy Grail of reproductive immunology has
been to elucidate the fundamental processes that explain fetal survival in all mammalian species. Consequently, investigators have sought experimental evidence
arguing definitively for or against each of Medawars three hypotheses. The field
has been reviewed comprehensively in the context of these three guiding hypotheses. The key issue of whether a single mechanism explains Medawars paradox
has not been answered decisively, and it seems likely that no single mechanism
completely resolves the paradox. An overview of the current literature reveals no
broad agreement on which fundamental processes resolve Medawars paradox for
all mammalian species. Nevertheless, compared to surgically transplanted tissue
allografts, ample evidence suggests that the fetus enjoys special privileges and
employs specific procedures to evade or minimize the risk of being rejected by
the maternal immune system during gestation.

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During the discussion that follows we use the paradigm of the fetus as a tissue
allograft tolerated by the mother, contrasting the immunological situation of a
fetus with that of a tissue allograft surgically transplanted onto a nontolerant
(allogeneic) recipient. Although some commentators now question the value of
this comparison (1, 5), it is a useful starting point to consider the immunogenetics
and immunobiology of the maternal-fetal relationship. To mimic the immunogenetics of pregnancy, the hypothetical donor graft should express two haploid
genotypes (paternal x maternal, F1) and the recipient should match one donor
haplotype (the maternal genotype). To aid our discussion, we provide a diagram
comparing processes in the afferent (antigen presentation leading to T cell activation) and efferent (T cell differentiation, migration, and effector functions)
phases of a T cell response that lead to T cellmediated rejection of tissue allografts (Figure 1). We consider whether these processes occur or are moderated
during gestation to explain fetal allograft survival. This diagram is based on current knowledge of processes that provoke T cell activation leading to tissue allograft destruction and rejection after transplantation (14, 15).

Fetal Loss Syndromes and Immune Dysregulation


Spontaneous Fetal Loss in Mice After genetic considerations, the most important reason for viewing the fetus as a tissue allograft is experimental evidence
that maternal immune responses can cause spontaneous fetal loss in some mating
combinations. However, it has long been established that provoking a systemic
maternal T cell response against paternal MHC alloanantigens during murine
pregnancy does not induce fetal loss. These results were interpreted as evidence
that the fetus was impervious to attack, even when the afferent arm of the T cell
response was bypassed experimentally, and that local mechanisms provided protection from effector T cells in such circumstances.
Even though the fetus is a de facto tissue allograft, spontaneous fetal loss due
to maternal immunity is considered to be a rare event. Circumstantial evidence
suggests that some instances of spontaneous fetal loss are due to immunological
complications during pregnancy. For many years, the most compelling animal
model of immunologically mediated spontaneous fetal loss has been the murine
[CBA/J x DBA/2] mating combination in which between 20% and 50% of fetus
is resorbed by gestational day 13 (17). The critical importance of this precise
parental genetic combination, and the ability to suppress fetal loss by preimmunizing females with peritoneal macrophages or by prior mating to a BALB/
cJ male, point to an immunological component that contributes to this fetal loss
syndrome. NK cells and macrophages have been implicated as cellular mediators
of the syndrome and excessive nitric oxide (NO) and TNF-a release by decidual
mononuclear cells as effector mechanisms that become dysregulated in this strain
combination (18, 19). An indirect role for GM-CSF and, significantly, maternal
CD8` T cells in preventing NK cell-mediated fetal loss in this system has also
been suggested (20). Recent studies reinforce the connection between TNF-a

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Figure 1 T cell immunobiology of tissue allograft rejection compared to the situation of the fetus. Tissue alloantigens (Ag) are delivered
to draining lymph nodes (LN) by donor or host APCs (step 1) where they encounter nave T cells (Tn). This leads to T cell activation and
differentiation (step 2) into cytotoxic (Tc) and helper (Th1 and Th2) T cells. Effector T cells (Tc and Th1) recirculate to donor graft tissues
or help B cells to produce antibodies (Ig), which contribute to the destruction of cells of donor origin (step 3). Evidence that steps 13 are
subject to regulation during the maternal-fetal relationship are considered in detail in the text. Two additional steps are also considered; step
4, Th2 dependent suppression of Th1 and Tc effector T cells, and step 5, direct access of Tn to fetal tissues avoiding the need to circulate
through LN.

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release by decidual macrophages, which precedes fetal loss (21). These findings
send clear messages that cytokine imbalances associated with inappropriate activation of macrophages and NK cells of the innate immune system are detrimental
to fetal survival in this experimental model. Indeed, a recent review proposes to
categorize cytokines and growth/differentiation factors as either deleterious (TNFa, IFN-c, IL-2) or beneficial (TGF-b, LIF, CSF-1, GM-CSF, IL-1, IL-3, IL-4, IL6, IL-10 and IFN-s) to fetal survival, implying a link between regulated activation
of cells that produce the second set of factors and fetal survival in normal pregnancies (22). As yet, it is unclear how dysregulated activation of NK cells and
decidual macrophages relate to the distinctions made between fetal and tissue
allografts by maternal T cells. Moreover, how relevant these observations are to
successful pregnancy remains to be seen, originating as they do from a single
murine mating combination. Indeed, IFN-c (23) and nitric oxide (NO) (24) production by maternal monocytes and uterine NK cells (25) that invade the decidua
shortly after implantation are features of normal pregnancies in mice. One problem is that it is not obvious whether cytokine imbalances are caused by inappropriate T cell responses or vice versa. Chaouat et al showed that spontaneous fetal
loss in the CBAxDBA/2 model was corrected by administering IL-10 or the
unusual interferon variant IFN-s, which is expressed in ruminant placentas (26).
Collectively, these results point to a critical role for the local inflammatory milieu
at the maternal-fetal interface, which might shape the context in which maternal
T cells encounter fetal alloantigens. We discuss this issue in more detail later.
Connections between the activation status of the innate immune system and
human pregnancy outcomes have been reviewed recently (9).
An increasing number of reports document spontaneous fetal loss syndromes
in matings involving gene-deficient (knockout) mice. In some cases, these syndromes arise from defective placental vascularization or fetal development rather
than immune dysfunction and are not discussed here. Mice deficient in the production of myeloid growth/differentiation factors, granulocyte-macrophage colony stimulatory factor (GM-CSF) and macrophage colony stimulatory factor
(CSF-1 or M-CSF), both exhibit poor reproductive performance. In GM-CSF
gene-deficient mice, the effects manifest as poor placental development, which
increases the rate of fetal loss and compromises fetal growth (27). CSF-1 gene
deficient mice exhibit low pregnancy rates and small litter sizes that might indicate
immune dysfunction leading to fetal rejection. However, the major effect of CSF1 deficiency in spontaneously mutant osteopetrotic (op/op) mice is on the frequency and rate of ovulation (28). This highlights a major difficulty in using
gene-deficient mice to assess requirements for successful pregnancy since total
loss of a cytokine or growth factor may result in multiple effects, with cumulative
impacts on reproductive performance, without necessarily compromising immunological protection of the fetus. Another technical problem is that many investigators assess reproductive performance in syngeneic or at least MHC-matched
mating combinations because nearly all gene-deficient (knockout) mice are generated on the 129/Sj (H-2b haplotype) background, which are then intercrossed

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with H-2b haplotype C57BL/6 mice to establish the lineage. Given the importance
of assessing the potential immunological stress due to parental genetic disparity,
it is imperative to examine the effects of gene deficiencies in allogeneic as well
as syngeneic pregnancies. Linked to this, it may also be necessary to determine
whether the effects of gene deficiencies manifest only when inherited as maternal
and/or paternal traits rather than as traits inherited from both parents.
Induced Fetal Loss and Tryptophan Metabolism Increased rates of fetal loss
are induced by injecting pregnant mice with IL-2, which promotes Th1-type T
helper cell responses at the expense of Th2-type responses (29). This reinforces
the view that a delicate immunological equilibrium is established during gestation
that can be subverted by inappropriate activation of monocytes or lymphocytes
of the innate or adaptive immune systems (30). However, definitive proof that
maternal T cells specific for paternally inherited alloantigens could be induced to
participate in immune responses leading to fetal rejection was not obtained until
recently. Experimental evidence supporting this view was obtained from studies
in which pregnant mice carrying syngeneic or allogeneic fetus were treated with
a pharmacologic inhibitor of an enzyme called indoleamine 2,3 dioxygenase
(IDO) (31), which is expressed by cells in the maternal decidua (32) and which
catabolizes tryptophan (33). This treatment induced uniform loss of allogeneic
fetuses, which was complete by gestational day 9.5 when pregnant mice were
exposed to IDO inhibitor at gestational day 4.5, the time of blastocyst implantation. Further, the same treatment had no effect on development to term of syngeneic fetus or allogeneic fetus carried by immunodeficient RAG-1 gene-deficient
mothers, which have no lymphocytes. The rationale for these experiments came
from studies on immunosuppressive human macrophages that prevent T cell activation in vitro by depriving T cells of tryptophan (34). These findings demonstrate
that allogeneic fetus are potentially vulnerable to maternal T celldependent processes that could provoke fetal loss, and cells expressing IDO and degrading
tryptophan provide protection from maternal T cells. Interestingly, golden hamsters placed on high tryptophan diets exhibited high rates of fetal loss in an earlier
study (35). This study was designed to test whether increased synthesis of serotonin analogues derived metabolically from dietary tryptophan would induce
rapid fetal loss due to non-immunological, pharmacologic effects on the placenta.
However, the outcome obtained can also be interpreted in terms of a link between
tryptophan metabolism and immunological protection of allogeneic fetus during
gestation. More studies are needed to determine whether these findings can be
generalized to other mouse mating combinations and to other mammalian species,
including humans. However, the observation that serum tryptophan levels
decrease progressively from the first trimester of human pregnancy provides circumstantial evidence that this link may be relevant to human pregnancy (36).
Recurrent Spontaneous Abortion in Humans Spontaneous human fetal loss is
a significant clinical problem. Some commentators estimate that early fetal loss

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after implantation may occur in as many as 30% of human pregnancies since


many may not be diagnosed (6). Moreover, approximately 6070% of spontaneous abortions in women are unexplained by fetal defects or infections. Studies
on recurrent spontaneous abortion syndromes are dominated by suggestions of
immunologic causation or at least observations that can be interpreted as such.
This evidence includes genetic (epidemiological) analyses, anatomical, physiological, and cell biological analyses, and evidence for cytokine dysregulation
linked to inappropriate activation of the innate and adaptive immune systems
during human pregnancy. Wegmann and colleagues suggested that Th2-type cytokines and T helper cell responses correlated with successful pregnancy outcomes
(37, 38). Recent reports provide additional support for this hypothesis (6, 39).
Although beyond the scope of the present review, these issues are discussed in
depth by others (6, 30, 40, 41). Summarizing the current state of the field, there
are compelling reasons for assuming that some, perhaps many, of human pregnancy failures are causedby immune dysfunction that upsets the delicate balance
between maternal tolerance and fetal nurturing. However, it is very difficult to
discriminate whether abnormalities observed during difficult pregnancies are
causes or effects of immune dysfunction. Given the largely and necessarily
descriptive nature of the evidence available from studies on human pregnancy, it
is difficult to assess definitively whether maternal T cells are participants, facilitators, or merely bystanders in processes that lead to postimplantation loss of
human fetuses .
Immunological dysfunction has also been suggested as a potential cause of the
hypertensive disorder pre-eclampsia, which manifests late in human pregnancy
(4244). However, maternal age and parity, male factors (45), and defective endothelial and vascular tissue development (46) have all been considered as factors
that predispose to pre-eclamptic pregnancy, although it is difficult to know which
factors predispose toward the syndrome and which are effects.A recent radical
suggestion is that pre-eclampsia is far more frequent when partners cohabit for
only a brief period before conception compared with partners who have a long
history of cohabitation (44, 47). While this observation needs to be confirmed, it
raises intriguing questions about mechanisms that would decrease the likelihood
of problematic pregnancy during a lengthy period of cohabitation. Although speculative, one answer might be that exposure to sperm may precondition the female,
perhaps even her immune system, if genetic material from sperm induces immunosuppression or tolerance over time.

THE IMMUNOBIOLOGY OF FETAL SURVIVAL AND


GRAFT REJECTION
In this section we compare and contrast fetal implantation and growth in the uterus
during gestation with the immunobiology of T cellmediated allograft rejection
(Figure 1). Using this approach we address Medawars paradox of the tissue

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allograft and describe recent experimental data that relate to regulation of maternal
T cell responsiveness during pregnancy. Our discussion focuses on studies of
murine pregnancy, which are amenable to genetic manipulation and intense
immunological scrutiny. We also discuss how immunological knowledge gained
from studying pregnancy might apply more generally to understanding T cell
regulation in other immunological phenomena.

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T CellMediated Tissue Allograft RejectionA Brief


Synopsis
Tissue allografts transplanted onto recipients that are not T cell deficient or immunosuppressed are rejected, after a delay of several days to a few weeks (Figure
1). During this period, donor alloantigens are delivered by specialized antigen
presenting cells (APCs) of myeloid origin to draining lymph nodes (step 1, afferent phase). There, APCs encounter and activate nave T cells that recognize donor
alloantigens, which proliferate and differentiate into helper and cytotoxic effector
T cells (step 2). Effector T cells recirculate to the grafted donor tissue where they
kill cells displaying donor alloantigens, which eventually destroys the graft (step
3, efferent phase). T cells also coordinate B cell activation and production of
complement-fixing antibodies that bind to donor cells. Recent reviews are available for readers wishing to know more about the details of these processes (15,
4850).
Interactions between the adaptive and innate immune systems at the cellular
and molecular level regulate the T cell response to tissue allografts. In particular,
myeloid cells play critical roles in regulating each stage of this entire process.
Dendritic cells (DCs) are specialized to accumulate antigens at the site of tissue
engraftment, to migrate to draining lymph nodes, and to present antigens under
conditions that provoke T cell activation. Although immunologists have largely
focussed on elucidating mechanisms that generate effective T cell responses, there
has also been interest in addressing how T cell responses are regulated to prevent
loss of control leading to autoimmunity, which would inflict collateral damage
on healthy (host) cells and tissues. The concept of immunosuppression grew out
of the realization that there must be mechanisms that limit immune responses
spatially and temporally to minimize the risk of autoimmunity. We discuss the
critical role of inflammation and immunoregulatory processes during pregnancy
later. However, the unqualified term inflammation is, in our opinion, inadequate
to describe the complex processes that occur in tissue microenvironments undergoing immune attack. We prefer the concept of aggressive and suppressive
inflammatory processes, which co-exist temporally and even spacially, and counterbalance one another. We envisage that the outcomes of immune responses
targeted to particular tissue microenvironments are critically dependent on the
precise nature of the cellular processes, molecular cues, and biochemical status
of microenvironments as perceived by nave or effector T cells. By these criteria
it is more important to know whether the collective effect of all these processes

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tends to promote or suppress T cell responses in vivo than to measure individual


components that may be overruled by other processes in the complex milieu of
inflamed tissues. Thus, the overall balance of this milieu dictates the outcome and
direction of T cell responses.

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Preparing For EngraftmentPre-Implantation Processes


Unlike recipients of surgically transplanted tissue allografts, females experience
many physiological changes before blastocyst implantation takes place. Three
events, which are necessary preludes to implantation and pregnancy, trigger these
changes: ovulation, copulation, and fertilization. These events directly or indirectly induce dramatic changes in metabolism and the hormone and cytokine
balance in the reproductive tract, which is thereby prepared for subsequent blastocyst implantation. Many changes in uterine physiology that occur following
these events resemble classical inflammation at the mucosal surfaces of the female
reproductive tract, and it is quite likely that these changes impact locally on the
maternal immune system well before the blastocyst implants in the uterus. Consequently, the outcome of interactions between T cells and myeloid cells are likely
to differ markedly during pregnancy, compared to outcomes in nonpregnant hosts.
These distinctions are likely to be most acute at mucosal surfaces lining the female
reproductive tract and in lymph nodes draining the maternal-fetal unit. Thus, the
uterus may be preconditioned to accept the blastocyst (the incoming tissue allograft).This situation contrasts with that of a surgically inserted tissue allograft
because there is no prior conditioning of the graft bed or draining lymph nodes
in graft recipients.
Hormonal changes precede implantation and persist throughout gestation. Steroid hormones induced by ovulation are potent modulators of myeloid APC and
lymphocyte functions and may influence the nature and potency of immune
responses during pregnancy (51, 52). For example, progesterone, the hallmark of
pregnancy, suppresses T cell effector functions by modulating potassium channels
and calcium signaling, which affects gene expression (53).
Male factors, the consequence of exposure to sperm or semen, may also trigger
events that have beneficial effects favoring successful pregnancy outcomes (45).
Sperm or components of semen could elicit physiological changes, for example
via prostaglandins, that promote immunosuppression at the mucosal surfaces of
the female reproductive tract (5, 54). In addition, Tremellen et al demonstrated
that transforming growth factor (TGF-b1), a component of seminal fluid, stimulates GM-CSF production and recruitment of inflammatory cell infiltrates into the
uterus (55).

Nurture Without ImmunityPostimplantation Fetal


Development
After implantation, the key immunological questions are whether maternal T cells
are aware of fetal alloantigens that would provoke immune responses if presented
on a paternal tissue graft, and, if they are, why does this not lead to fetal loss

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during gestation? The frequency of fetus-specific maternal T cells is a significant


fraction (;1030%) of the peripheral T cell repertoire in most parental combinations in outbred populations because of MHC mismatch. This explains why
tissue allografts provoke potent anti-graft T cell responses and why maternal
acceptance of the same alloantigenic differences is such an intriguing issue to
immunologists.
Maternal T Cell Awareness of Fetal Alloantigens During allogeneic pregnancy
the maternal immune system contains nave T cells that are not tolerized to fetal
alloantigens and yet do not attack the fetus. An explanation for maternal acceptance of the fetus during gestation is that either maternal T cells are not exposed
to fetal alloantigens or exposure occurs but results in T cell tolerance rather than
immunity. Several studies involving female T cell receptor (TCR) transgenic mice
mated with allogeneic males provide strong evidence that maternal T cells are
aware of fetal alloantigens during pregnancy. Using this approach, Tafuri et al
demonstrated that maternal H-2Kb-specific CD8` T cells were functionally tolerized by fetal H-2Kb alloantigen, but that this state lasted only until shortly after
parturition (56). Using another H-2Kb-specific system, we have reported similar
phenotypic changes during allogeneic pregnancy (57). In a third study, Jiang &
Vacchio concluded that maternal male-(H-Y)-antigen-specific CD8` T cells were
tolerized by Fas-dependent deletion mediated by fetal trophoblast cells, and by
nondeletional processes that rendered residual maternal T cells unresponsive to
antigenic challenge in vitro (58).
The conclusion that maternal T cells are aware of fetal alloantigens, at least
in murine pregnancy, has several important implications that relate to Medawars
three postulates to explain fetal survival despite potential maternal immunity.
First, no cell-impermeable barrier between mother and fetus prevents exposure
of fetal alloantigens to maternal T cells throughout gestation. Second, antigenic
immaturity of the fetus does not explain why maternal T cells fail to mount a
response to the fetus. And third, fetal survival depends on tolerogenic mechanisms
that block maternal T cell responses. For obvious practical and ethical reasons it
is not possible to conduct similar experiments in humans; however the recently
developed ability to focus on fetal-specific maternal T cells in peripheral blood
using highly specific MHC/peptide tetramer reagents may aid experimental analyses of the effect of pregnancy on these cells (59).
Fetal Cell Traffic into Maternal Circulation The highly organized trophoblast,
endothelial and mesenchymal cells that form the outer trophoblast, segregate fetal
and maternal blood circulatory systems (5, 60). As well as physical barriers,
molecular (24) and biochemical (31) barriers may also prevent the passage or
functioning of maternal T cells that attempt to access fetal tissues. However,there
is general agreement that the barrier to cellular and subcellular traffic between
mother and fetus is not completely impermeable during human or rodent pregnancy, and the maternal or host immune system is alerted to the presence of

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foreign alloantigens during pregnancy and after tissue engraftment (5, 60, 61).
Thus, while the anatomical organization of the maternal-fetal interface may have
evolved at least in part to minimize immunological contacts, this is an imperfect
strategy necessitating additional mechanisms to ensure fetal survival during gestation. The experiments cited above demonstrating maternal T cell awareness of
unprocessed fetal H-2Kb alloantigen (56, 57) or male H-Y peptide bound to unprocessed H-2Db (58) imply that fetal cells expressing MHC alloantigens alert maternal T cells to the presence of fetal MHC alloantigens. (A less likely explanation
which cannot be entirely ruled out is that MHC alloantigens shed from fetal cells
attach to maternal APCs.) Thus, the conclusion from these studies is that either
maternal T cells encounter fetal cells as they circulate through the maternal-fetal
unit (Figure 1, step 5) or fetal cells migrate to local draining lymph nodes where
they present fetal alloantigens to maternal T cells (step 2).

Antigenic Immaturity of the Fetus As pointed out by Medawar over four


decades ago, a simple explanation for lack of maternal immune responses during
pregnancy is a lack of MHC expression on fetal tissues during gestation (10).
This assumes that the maternal-fetal interface is the only point of contact between
maternal lymphocytes and fetal alloantigens. Murine trophoblast cells express
MHC class I genes and alloantigens at high levels from early times in gestation
when MHC class I expression is barely detectable on fetal tissues (62, 63). As
pointed out by other commentators, it is highly unlikely that maternal T cells
circulating through the murine maternal-fetal interface do not encounter cells of
fetal origin (60). Thus, this pattern of MHC class I expression at the maternalfetal interface is incompatible with the hypothesis that fetal tissues at the interface
are antigenically immature to minimize the risk of provoking maternal T cell
responses.
Nevertheless, it is important to stress that there is general agreement that MHC
class II alloantigens are not expressed by cells of fetal origin at the maternal-fetal
interface in humans or rodents (6466). This removes a critical factor that elicits
potent CD4` T cell responses, which are significant components of effector and
helper T cell responses that target tissue allografts leading to rejection (Figure 1,
step 3) (15). In this respect, the argument that antigenic immaturity contributes
to fetal survival has merit. It remains to be seen whether fetal loss ensues if
allogeneic MHC class II expression is forced on fetal trophoblast cells, for example in transgenic mice. Several studies report attempts to express MHC class II
molecules in trophoblast cells following DNA transfection of cultured trophoblast
cell lines (67) or to force MHC class II expression in murine trophoblast (68
70). It is not clear whether these attempts succeeded in transgenic mice because
it was not reported whether surface MHC class II expression was observed in
trophoblast cells in mice carrying a transgene with a strong CMV promoter. However, under normal circumstances MHC class II expression on murine trophoblast
is strongly repressed at the transcriptional level (71).

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The observation that human trophoblast cells express the nonclassical and
relatively nonpolymorphic MHC class I molecules HLA-G and, possibly, HLAE has inspired much research and speculation about their immunological significance, particularly with respect to their possible effect on maternal T cell
responses (66, 72). Recently, debate has focussed on their possible roles in regulating NK cell activity, rather than T cell responses (73, 74). This debate is
difficult to evaluate experimentally, largely because analogous MHC-like molecules and their receptors have not yet been identified in rodents. This last point
suggests either that immunological roles for HLA-G/E may have evolved after
rodent and primate ancestors diverged, or that rodent and human NK cell receptors
are no longer homologous. Perhaps these possible roles, if they can be demonstrated experimentally, are examples of processes that evolved due to the need to
protect more fetal mass for longer periods in larger mammalian species.
Fetal Microchimerism In the field of transplantation research, energetic efforts
are currently directed at the therapeutic potential of induced microchimerism for
prolonging survival of tissue grafts (75, 76). In pregnancy, maternal T cell tolerance must be induced and maintained either by fetal trophoblast cells or by
fetal cells that enter the maternal circulation and establish a reservoir of fetal cells
in maternal tissues that is either stable or continuously replenished. At present, it
is not clear which route is most critical. However, recent studies have generated
compelling evidence that fetal microchimerism affects the maternal immune system. Studies on pregnant women show that fetal cells appear in maternal circulation at an early stage in gestation and that genetic microchimerism persists for
many years after parturition (7780). An earlier study on pregnant mice by Bonney & Matzinger demonstrated that male fetal cells containing Y-chromosomal
DNA access maternal circulation in about 20% of immunocompetent mice and
in a higher proportion (;40%) of immunocompromised mice (60). These observations prompted the authors to conclude that fetal microchimerism could not
explain maternal T cell tolerance and that maternal T cell immunity eradicated
all traces of fetal cells in maternal circulation in most cases. However, this conclusion would seem incompatible with data showing that maternal splenic T cells
not only are aware of fetal alloantigens but are tolerized to them in all pregnant
mice (5658). These results can be reconciled by assuming that fetal cells migrating into maternal tissues excite a T cell response that results in T cell tolerance
and destruction of the fetal cells.This scenario might also help to explain why
maternal tolerance disappears shortly after parturition, in the study by Tafuri et
al, since a continuous supply of fetal cells may be necessary to maintain T cell
tolerance (56); T cell tolerance did, however, persist after parturition, as reported
in the recent study by Jiang & Vacchio (58).
More speculatively, it has also been suggested that circulating fetal cells may
help induce or maintain thymic involution that persists during human and animal
pregnancy, and that this may contribute to maternal T cell tolerance of the fetus
(81, 82) (although it is difficult to eliminate neuroendocrine effects and nonspe-

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cific effects of steroid hormones released during pregnancy as factors contributing


to thymic involution). Nevertheless, modification of thymic output through microchimerism is an active field of current research as an potential therapy to improve
the success rate of tissue allografts (83). At present, however, there is no consensus on whether thymic microchimerism is beneficial or detrimental to the outcome
of tissue transplantation (84). Thus, there is no compelling evidence that modifications to maternal thymus output during pregnancy makes significant contributions to maternal T cell tolerance of the fetus.
Maternal T Cell Tolerance The mechanisms that induce maternal T cell tolerance are not understood in detail, although there is some progress from recent
studies on pregnant TCR transgenic mice, as reviewed above. Tolerance induction
is likely to be linked to the unique cocktail of hormones and cytokines that are
elaborated before and after blastocyst implantation. The nature of inflammatory
changes that occur during pregnancy and their potential impact on maternal T
cell responsiveness are discussed in detail in the next section. These, or other
factors, might modify the afferent (Figure 1, steps 1, 2) or effector (steps 3, 4)
arms of the immune response elaborated against tissue allografts. As alluded to
above, pregnancy correlates with enhanced Th2-type responses (step 4), which
may help to ameliorate potentially lethal Th1 and cytotoxic (Tc) T cell responses
(6, 38, 85). Thus, encounters between APCs displaying fetal alloantigens may
induce T cell deletion or anergy or enhance CD4` Th2-type responses. Jiang &
Vacchio recently reported that maternal H-Y-specific CD8` T cells were either
deleted, via Fas-dependent processes, or anergized during pregnancy (58). However, this result is inconsistent with reports going back many years that pregnancy
does not suppress systemic T cell immunity to paternal tissue allografts or cells
expressing paternal MHC alloantigens. Two potential explanations for this discrepancy are the weak nature of the single fetal alloantigen under scrutiny (11)
or the absence of T cells that do not express the H-Y-specific TCR clonotype on
CD8` T cells (58). It should also be emphasized that tumor cells used by Tafuri
et al to detect maternal T cell tolerance in their experimental system (56) are less
immunogenic than tissue allografts and therefore much easier to tolerate. To reconcile earlier experiments showing lack of systemic T cell tolerance with those
of Tafuri et al, it is necessary to postulate that T cell tolerance can be reversed in
vivo without compromising fetal development. This hints at a role for other protective mechanisms operating locally at the maternal-fetal interface that can prevent activated effector T cells from attacking fetal cells (Figure 1, step 3).
Antigenic immaturity of fetal trophoblast cells or local immunosuppression at the
maternal-fetal interface could contribute to continuing survival of the fetus under
such circumstances. As discussed in the next section, a final tolerogenic phenomenon that might contribute to the onset of transient maternal T cell tolerance
during gestation is linked suppression by maternal T cells that become anergized
in early encounters with cells displaying fetal alloantigens. This is analogous to
experimentally induced long-term T cell tolerance (also termed infectious toler-

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ance) induced in vivo when nave T cells encounter APCs in the presence of
nondeleting monoclonal antibodies that block T cell activation (86).

THE ROLE AND NATURE OF INFLAMMATION


DURING PREGNANCY

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The Role of Inflammation in Adaptive Immune Responses


The immune system can be conceptually divided into the adaptive systemT
and B cells, which respond to specific antigensand the innate system, which
responds to a wide range of signals of infection and injury in an antigenindependent fashion. The adaptive system confers exquisite specificity and memory, while the innate system provides most of the actual inflammatory and effector
functions needed for the organism to fight infection. A decade ago, Janeway
pointed out that although the adaptive immune system is a marvel of flexibility
and precision, immunization with foreign antigen nonetheless requires a crude,
proinflammatory adjuvant in order to elicit an adaptive response. Janeway thus
proposed that costimulatory signals from the innate immune system, indicating
that infection was present, were necessary in order to give permission to the
adaptive immune system to activate. By extension, tissues that were not infected
or inflamed would not support lymphocyte activation and would thus operationally be considered self regardless of the antigens they displayed (87).
Janeways hypothesis has been extended to include any signals that indicate
microenvironmental tissue injury, not just infection (88), and Matzinger has proposed that any condition that the immune system recognizes as connoting danger
to the host could be permissive for lymphocyte activation (89). Fearon has pointed
out that, far from being a primitive first line of defense, the innate immune system
actually acquires critically important information regarding the nature of the threat
to the host via its array of specialized receptors to detect microbial products, tissue
damage, complement activation, clotting factors, etc (90). Thus, it makes sense
that the highly specialized recognition and memory functions of the adaptive
system should be regulated and directed by the older and wiser innate immune
system (91).
A growing body of evidence now supports the view that the adaptive immune
response is regulated by the innate system. While the perspectives cited above
differ in their emphasis, they have in common the concept that lymphocyte
responses are not simply driven by encounter with antigen, but rather are strongly
influenced by the context in which this encounter occurs. As a general principle
in these models, inflammation favors activation. However, in the case of pregnancy this presents a difficulty, since the decidua would appear to be a highly
reactive tissue, both at implantation and throughout gestation, with many signs
of inflammation (reviewed in 3). Why does this not favor activation of alloreactive
maternal T cells and rejection of the fetus?

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Not All Inflammation Is the Same


One clue may come from the particular nature of the inflammatory response
provoked by the fetus. It has been shown using models of infectious disease that
the nature of the initial inflammatory response strongly influences the subsequent
adaptive response. Infection of susceptible mouse strains with the parasite Leishmania major induces inflammation and a strong immune reaction, but the result
is almost entirely a Th2 and humoral response, which is not protective against
this intracellular pathogen. In contrast, when the initial inflammatory milieu is
altered by infection or immunization with Leishmania in the presence of IL-12,
the result is primarily a Th1 response, which is protective (92, 93). Thus, the
nature of the initial innate response is critical in determining the nature of the
subsequent adaptive response.
In pregnancy, the maternal-fetal interface is an immunologically active site,
with the production of many immunoregulatory cytokines. Several recent reviews
have drawn together the considerable evidence that this cytokine milieu predominantly favors development of Th2 responses. As discussed above, in a number of settings, Th2 cytokines have tended to promote successful pregnancy,
whereas Th1 cytokines incline toward fetal loss (6, 38). While this model has
been somewhat more clean cut in mice than in humans, the available evidence
supports at least a circumstantial link in humans as well (85).
Moreover, the concept that different types of inflammation lead to different T
cell responses need not be confined to the Th1/Th2 paradigm. In the immune
system, there are numerous examples of one inflammatory stimulus triggering a
counterregulatory response, which limits the damage done by the initial agent
e.g., pretreatment with TNF protects against subsequent lethal challenge with
TNF or IL-1 (94), and pretreatment with IL-12 protects against rechallenge with
IL-12 (95). In this regard, IFNc is particularly interesting. Data from IFNc and
IFNc-receptor knockout animals reveal that, while they are defective in their
ability to clear microbial pathogens, as would be expected from the loss of a proinflammatory cytokine, they are also unexpectedly resistant to tolerance induction
(9698) and susceptible to a variety of autoimmune disorders (99101). This
suggests that IFNc is also important in recruiting counterregulatory systems that
limit inappropriate or excessive T cell activation.
Conceptually, such opposing regulatory systems are often thought of as proinflammatory and anti-inflammatory responses. In reality, however, from the
point of view of the innate immune system, both reflect proactive recruitment of
effector cells and cytokine networks, and hence both can be legitimately considered forms of inflammation.It is only from the point of view of the T cell that
certain types of inflammation appear immunosuppressive. We propose that in
pregnancy the innate immune system is activated, local and systemic inflammation occurs, and the adaptive immune system is fully aware of paternal alloantigens, butunlike the case of an organ allograftthe nature of the inflammatory

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response is such that this awareness of antigenic difference is not allowed to lead
to fetal rejection.

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What Is Different About the Inflammatory Milieu


in Pregnancy?
As outlined in Figure 1, there are several potential points at which the mammalian
fetus could differ from a simple paternal tissue allograft. The first (labeled Step
1 in the Figure) is in antigen presentation. Although studies in mice indicate that
the maternal immune system becomes aware of fetal antigens during gestation, it
is not clear by what route these antigens are presented. As discussed above, fetal
tissues such as trophoblasts suppress expression of MHC class II and have reduced
or absent MHC class I. Those alloantigens, which are expressed on trophoblast,
may be presented in an incomplete or immunosuppressive fashion (e.g., without
costimulatory signals). Likewise, local maternal APCs such as decidual macrophages may be ineffective or tolerogenic presenters of fetal antigens. However,
since there is strong evidence that the maternal immune system also encounters
fetal antigens outside of the specialized setting of the placenta (see above), additional mechanisms must exist to prevent maternal sensitization and fetal rejection.
We have alluded to the apparent Th2 bias in pregnancy which may help protect
against rejection. That bias might be introduced locally at the maternal-fetal interface, e.g., by factors such as IL-4, progesterone, or PGE2 (37, 52, 102). Alternatively, the bias may be introduced regionally in the lymph nodes draining the
uterus. Recent studies suggest that lymph nodes which drain sites of mucosal
tolerance are instrumental in tolerance induction and are functionally different
from lymph nodes draining nontolerogenic sites (103). The mechanism by which
this difference is introduced has not been established, but the regional lymph
nodes draining the uterus are potential sites of tolerance induction or Th2 bias.
Finally, there could in theory be a systemic Th2 bias introduced by circulating
cytokines or pregnancy-related hormones. This last possibility is the most problematic, since it must be reconciled with the fact that pregnant females mount
successful Th1-type responses to infectious agents and skin grafts.
Even if potentially cytotoxic T cells are generated by exposure to fetal antigens, the uterine microenvironment may suppress development of effector function (step 3 in Figure 1). PGE2 and cytokines such as IL-10 and TGFb can
suppress T cell activation and proliferation and are found in placenta. For example, in the CBA x DBA/2 murine model of recurrent fetal loss, there is a local
defect in placental IL-10 production, and systemic administration of IL-10
restores the ability of abortion-prone females to carry to term (26).
In addition to soluble suppressive factors, there may also be structural features
of the maternal-fetal interface that confer some degree of immune privilege. Hunt
et al have described fas-ligand (fas-L) expressed in uterus and placenta, and have
demonstrated increased leukocyte infiltrate into the maternal-fetal interface of fasL deficient (gld) mice (104). Although this infiltrate was composed of granulo-

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385

cytes and was not antigen-driven (matings were syngeneic), it nonetheless raises
the possibility that Fas-L could modulate local T cell activation in the placenta.
Likewise, IDO has been described at the maternal-fetal interface in human placenta (32), where it may serve an immunosuppressive role (31).
Finally, the most recent and controversial suggestion concerning maternal tolerance of the fetus asks whether there may be a systemic perturbation of specific
T cell responses to fetal antigens. There is growing agreement that naive T cells
that do not receive their initial activation under the normal (i.e., proinflammatory)
conditions may be rendered unresponsive or anergic (reviewed in 105). Under
certain circumstances, tolerized or anergized T cells may spread their unresponsiveness to other T cells recognizing the same antigen or to additional clones
recognizing different, linked antigens (106, 107; and reviewed in 86). The mechanisms of these phenomena are not fully understood, but they suggest that there
may exist antigen-specific tolerogenic mechanisms independent of the general
bias toward Th2 in pregnancy.
Evidence that such tolerogenic mechanisms might operate during pregnancy
has been discussed above. Taken together, these findings suggest that the T cell
repertoire capable of responding to fetal antigens is made aware of the presence
of these antigens during pregnancy and rendered unresponsive to them in an
antigen-specific manner. Whether this condition arises by direct exposure of all
potentially responsive cells to antigen under tolerizing conditions or by tolerization of a subset of T cells with subsequent spread to the remainder of the repertoire
remains to be determined.

CONCLUSIONS
We propose that the key difference between the fetal allograft and a solid-organ
transplant lies not in the ability of the adaptive immune system to see and respond
to fetal alloantigens, but rather in the way in which the innate immune system
treats the presence of the fetus. The innate system is alerted and responds actively
to the fetal invasion, but the type of inflammation jointly created by fetally
derived cells and the maternal innate immune system is not a milieu in which
rejecting T cell responses are produced. However, far from being hidden from
the maternal adaptive immune system, fetal alloantigens are actively involved in
establishing a condition of antigen-specific tolerance during pregnancy.

ACKNOWLEDGMENTS
These studies were supported by grants AI44219. AI42247, HL60137, and
AI44759 from the National Institutes of Health, the Departments of Medicine and
Pediatrics, Medical College of Georgia and generous support from the Trustees
of the Carlos and Marguerite Mason Trust.

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Annual Review of Immunology


Volume 18, 2000

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CONTENTS
Discovering the Role of the Major Histocompatibility Complex in the
Immune Response, Hugh O. McDevitt
Receptor Selection in B and T Lymphocytes, David Nemazee
Molecular Basis of Celiac Disease, Ludvig M. Sollid
Population Biology of Lymphocytes: The Flight for Survival, Antonio A.
Freitas, Benedita Rocha
Nonclassical Class II MHC Molecules, Christopher Alfonso, Lars
Karlsson
Negative Regulation of Cytokine Signaling Pathways, Hideo Yasukawa,
Atsuo Sasaki, Akihiko Yoshimura
T Cell Activation and the Cytoskeleton, Oreste Acuto, Doreen Cantrell
The Specific Regulation of Immune Responses by CD8+ T Cells
Restricted by the MHC Class Ib Molecule Qa-1, Hong Jiang, Leonard
Chess
The Biology of Chemokines and their Receptors, Devora Rossi, Albert
Zlotnik
Dendritic Cells in Cancer Immunotherapy, Lawrence Fong, Edgar G.
Engleman
CD8 T Cell Effector Mechanisms in Resistance to Infection, John T.
Harty, Amy R. Tvinnereim, Douglas W. White
Glucocoricoids in T Cell Development and Function, Jonathan D.
Ashwell, Frank W. M. Lu, Melanie S. Vacchio
Molecular Genetics of Allergic Diseases, Santa Jeremy Ono
Immunology at the Maternal-Fetal Interface: Lessons for T Cell Tolerance
and Suppression, A. L. Mellor, D. H. Munn
Regulation of B. Lymphocyte Responses to Foreign and Self-Antigens by
the CD19/CD21 Complex, Douglas T. Fearon, Michael C. Carroll,
Michael C. Carroll
Regulatory T Cells in Autoimmunity, Ethan M. Shevach
Signal and Transcription in T Helper Development, Kenneth M. Murphy,
Wenjun Ouyang, J. David Farrar, Jianfei Yang, Sheila Ranganath,
Helene Asnagli, Maryam Afkarian, Theresa L. Murphy
The RAG Proteins and V (D) J Recombination: Complexes, Ends, and
Transposition, Sebastian D. Fugmann, Alfred Ian Lee, Penny E. Shockett,
Isabelle J. Villey, David G. Schatz
The Role of the Thymus in Immune Reconstitution in Aging, Bone
Marrow Transplantation, and HIV-1 Infection, Barton F. Haynes, M.
Louise Markert, Gregory D. Sempowski, Dhavalkumar D. Patel, Laura
P. Hale
Accessing Complexity: The Dynamics of Virus-Specific T Cell
Responses, Peter C. Doherty, Jan P. Christensen
The Role of Chemokine Receptors in Primary, Effector, and Memory
Immune Responses, Federica Sallusto, Charles R. Mackay, Antonio
Lanzavecchia
Phosphorylation Meets Ubiquiination: The Control of NF-Kappa-B
Activity, Michael Karin, Yinon Ben-Neriah
Reservoirs for HIV-1: Mechanisms for Viral Persistence in the Presence
of Antiviral Immune Responses and Antiretroviral Therapy, Theodore
Pierson, Justin McArthur, Robert F. Siliciano

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Regulation of Antibody Responses via Antibodies, Complement, and Fc


Receptors, Birgitta Heyman
Multiple Roles for theMajor Histocompatibility Complex Class I--Related
Receptor, FcRn, Victor Ghetie, E. Sally Ward
Immunobiology of Dendritic Cells, Jacques Banchereau, Francine
Briere, Christophe Caux, Jean Davoust, Serge Lebecque, Yong-Jun Liu,
Bali Pulendran, Karolina Palucka
An Address System in the Vasculature of Normal Tissues and Tumors,
E. Ruoslahti, D. Rajotte
Genomic Views of the Immune System, Louis M. Staudt, Patrick O.
Brown

767

Viral Subversion of the Immune System, Domenico Tortorella, Benjamin


E. Gewurz, Margo H. Furman, Danny J. Schust, Hidde L. Ploegh

861

DNA Vaccines: Immunology, Application, and Optimization, Sanjay


Gurunathan, Dennis M. Klinman, Robert A. Seder
Gamma Delta Cells: A Right Time and a Right Place for a Conserved
Third Way of Protection, Adrian C. Hayday

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