Immunity
Previews
of apoptosis that would promote cytokine
release by dying inflammasome-compe-
tent cells to promote tissue injury-
mediated inflammation, or whether the
release of oxidized mitochondrial DNA
and NLRP3 activation can occur in the
absence of apoptosis. Although the mito-
chondria is emerging as a key organelle
that senses cellular insults to promote
inflammatory responses, the role of
potassium efflux and the mechanisms
that drive mitochondrial ROS production
and control the release of mitochondrial
DNA are still unknown. Finally, it remains
to be determined whether release of
mitochondrial DNA into the circulation
upon tissue injury (Zhang et al., 2010)
could contribute to inflammasome activa-
tion by recruited phagocytes, thereby
B Cells, Not Just for Antibody Anymore
Kamal M. Khanna1 and Leo Lefrançois1,*
1Department of Immunology, Center for Integrated Immunology and Vaccine Research, UCONN Health Center, Farmington, CT 06030, USA
*Correspondence: llefranc@neuron.uchc.edu
DOI 10.1016/j.immuni.2012.02.011
B cell antibody production is thought to be crucial for protection against virus infection. In this issue of
Immunity, Moseman et al. (2012) illustrate an antibody-independent role for B cells in macrophage activation
that prevents virus dissemination after subcutaneous infection.
The production of neutralizing antibodies
by B cells to protect against viral and
bacterial infections is a hallmark of immu-
nity and one of the primary goals of vacci-
nation. However, recent reports including
a paper in this issue of Immunity have re-
vealed an additional previously unappre-
ciated critical function of B cells as regula-
tors of innate immunity to virus infection.
For some viruses, the very earliest events
after infection that lead to virus clearance
are not well defined. Whereas pre-existing
‘‘natural’’ antibody may in some cases
provide some degree of initial protec-
tion, the innate immune system including
macrophages, NK cells, and neutrophils
are believed to be central to limiting initial
pathogen spread while the adaptive im-
mune response ramps up. Moreover,
cytokines, in particular type I interferons,
are key to early protection against virus
contributing to inflammatory responses.
Given the important role of the NLRP3
inflammasome in various human patholo-
gies, the answer to these questions will
probably provide better overall under-
standing of the mechanisms that translate
cellular stress into an inflammatory
reaction. In Choderlos de Laclos’s
novel Dangerous Liaisons, relationships
are used as weapons in a game of power
and revenge that eventually takes a tragic
course. By analogy, when mitochondrial
DNA encounters and interacts with
NLRP3, it initiates a complex cascade of
events that start with inflammasome
formation and promotes self-defenses
or, in a dramatic twist worthy of Laclos,
backfires into a dangerous and harmful
inflammation.
infection. Thus, in the absence of type I
interferon receptor signaling, mice are
exquisitely sensitive to infection with a
number of viruses including vesicular
stomatitis virus (VSV) and mouse cyto-
megalovirus (MCMV) (Garcı́a-Sastre and
Biron, 2006). While plasmacytoid den-
dritic cells (pDCs) triggered through
pattern recognition receptors, particularly
TLRs, produce copious amounts of IFN-a
in response to virus infection, many other
cell types also have the ability to produce
and respond to type I interferons. Never-
theless, the precise mechanisms by
which IFN is induced, especially with re-
gard to the initial cell types that encounter
and potentially harbor virus replication,
are unclear.
In addition to TLR-mediated IFN-a
induction, TLR-independent pathways
for driving IFN-a production have also
Immunity 36, March 23, 2012 ª2012 Elsevier Inc. 315
REFERENCES
Martinon, F., Mayor, A., and Tschopp, J. (2009).
Annu. Rev. Immunol. 27, 229–265.
Menu, P., and Vince, J.E. (2011). Clin. Exp. Immu-
nol. 166, 1–15.
Nakahira, K., Haspel, J.A., Rathinam, V.A.K., Lee,
S.-J., Dolinay, T., Lam, H.C., Englert, J.A., Rabino-
vitch, M., Cernadas, M., Kim, H.P., et al. (2011).
Nat. Immunol. 12, 222–230.
Shimada, K., Crother, T.R., Karlin, J., Dagvadorj,
J., Chiba, N., Chen, S., Ramanujan, V.K., Wolf,
A.J., Vergnes, L., Ojcius, D.M., et al. (2012). Immu-
nity 36, this issue, 401–414.
Tschopp, J. (2011). Eur. J. Immunol. 41, 1196–1202.
Zhang, Q., Raoof, M., Chen, Y., Sumi, Y., Sursal,
T., Junger, W., Brohi, K., Itagaki, K., and Hauser,
C.J. (2010). Nature 464, 104–107.
Zhou, R., Yazdi, A.S., Menu, P., and Tschopp, J.
(2011). Nature 469, 221–225.
been described (Delale et al., 2005). For
example, the IFN-b response after CMV
infection has been shown to be regulated
by lymphotoxin (LT) produced by hemato-
poietic cells. In the absence of LTab-LTbR
signaling, mice are highly susceptible to
intravenous MCMV infection, resulting in
large part from poor induction of type I
interferons (Benedict et al., 2001). Re-
markably, the relevant source of LTb
is the splenic B cell (Schneider et al.,
2008). Bone marrow chimera recon-
stitution studies further revealed that the
responding cell type is a stromal cell of
nonhematopoietic origin. Thus, B cell-
derived LTb acting on a potentially in-
fected stromal cell drives IFN-b produc-
tion that leads to early protection against
infection. Additionally, this pathway of
IFN production is independent of TLR
signaling. Considering that these events
 Immunity

Previews

Now, in this issue of Immunity, Mose-

Presence of B cells Absence of B cells man et al. (2012) further dissect the role
VSV replication VSV replication of B cells, LT, type I interferons, and
+
CD169 macrophage (increased) +
CD169 macrophage (decreased) CD169+ macrophages in the draining LN
after subcutaneous VSV infection. First,
they show that B cells but not antibodies
are essential for protection against sub-
cutaneous VSV infection. Surprisingly,
although mice lacking immunoglobulin
LTα1β2 but harboring B cells die from intravenous
Type I IFN B cell Type I IFN (decreased) VSV infection, such mice are protected
from subcutaneous infection. In contrast,
Prevents VSV access VSV access mice lacking B cells succumbed to
to pheripheral nerves to pheripheral nerves and CNS subcutaneous VSV infection through virus
entry into the central nervous system via
peripheral nerves. Thus, infection via the
Figure 1. After Subcutaneous Infection with VSV, the Virus Is Initially Captured by CD169+ skin, perhaps mimicking virus transmis-
Macrophages in the Draining Lymph Node sion by an insect bite, reveals a clear
The release of LTa1b2 by B cells allows the CD169+ macrophages to tolerate increased replication of VSV, role for B cells in providing protection
possibly by inducing Usp18. This increased VSV replication induces the release of type I IFN by the
CD169+ macrophages, which in turn prevents the virus from accessing the peripheral nerves and traveling against a highly cytopathic virus, without
to the CNS by an undefined mechanism. In the absence of B cells there is a lack of LTa1b2 and without a requirement for antibody. Next, the
this, the virus fails to replicate in the CD169+ macrophages and type I IFN secretion is severely diminished. authors demonstrate that B cells but
The lack of type I IFN allows the virus to access the peripheral nerves, leading to dissemination of VSV to
the CNS.
again not antibody are required for
macrophage-dependent type I interferon
production. In this model, type I interferon
occur within minutes to a few hours after infection with VSV (Iannacone et al., is thought to confer protection via its
infection, these studies establish B cells 2010). These CD169+ macrophages are action on intranodal nerves to inhibit viral
as key regulators of early innate immunity the LN counterparts to the splenic replication. The precise mechanisms by
to CMV infection, independent of anti- CD169+ macrophages. Thus, this macro- which type I interferon affords this protec-
body production. phage subset represents a critical initial tion remain to be defined. Moreover, in the
In the case of vesicular stomatitis virus, barrier to viral and probably bacterial absence of B cells, LN macrophages did
a neurotropic member of the Rhabdovira- infection either through hematogenous not allow virus replication. Similar to
dae family that also includes rabies virus, delivery or through introduction into the studies in the spleen with CD169+ macro-
protection during primary and sec- skin. But do these cells directly destroy phages, previous work shows that VSV
ondary infections has long been ascribed virus or are cooperative efforts needed preferentially replicates in SCS macro-
to early neutralizing natural antibodies fol- from other innate and adaptive immune phages, rather than their medullary
lowed by induction of VSV-glycoprotein components? In the spleen, CD169+ counterparts. Indeed, in B cell-replete
(G)-specific IgM and subsequent class macrophages actually appear to promote but immunoglobulin-deficient mice, this
switching leading to IgG production. After viral replication (Honke et al., 2012). is precisely what is observed. Taken
intravenous infection, marginal zone met- Splenic CD169+ macrophages selectively together, the implication is that B cells,
allophilic macrophages (MMM) in the express the ubiquitin-specific protease but not antibody, are indispensable for
spleen capture the virus (Ciavarra et al., Usp18, which inhibits interferon ab re- promoting replication of VSV in SCS
2005). This initial line of cellular defense is ceptor (IFNAR) signaling. This inhibition macrophages leading to IFN production
vital to protection as indicated by the fact specifically in the CD169+ macrophages and protective immunity.
that depletion of splenic macrophages provides a more hospitable environment These intriguing data raise a number
results in virus dissemination and lethality for VSV replication. In IFNAR-deficient of important questions especially when
(Honke et al., 2012). B cell-derived LTab mice, all other splenic macrophage considered in light of earlier work indi-
is also required for splenic CD169+ macro- subsets allow VSV replication whereas in cating that splenic CD169+ macro-
phage organization (Mebius et al., 2004), normal mice, only the CD169+ macro- phages allow VSV replication through
further establishing an antibody-indepen- phages support virus growth. Moreover, mechanisms that inhibit IFNAR signaling
dent role for B cells in antiviral immunity. deletion of Usp18 results in lower splenic (Figure 1). Thus, although CD169+ macro-
More recently, the subcapsular sinus virus titers but rapid dissemination of the phages in both spleen and LN prefer-
(SCS) macrophages located in lymph virus to the central nervous system. entially allow VSV replication, whether
nodes (LN) have been shown to be essen- Honke et al. (2012) suggest that uncon- Usp18 mediates downmodulation of
tial for protection against subcutaneous trolled virus spread is caused by limited IFNAR signaling in LN SCS macrophages
VSV infection. Deletion of the SCS macro- neutralizing antibody production resulting needs to be examined to complete the
phages in the popliteal LN via injection of from poor initial virus replication in circuit. In addition, the possibility that
clodronate-loaded liposomes results in CD169+ macrophages, which is neces- LTa1b2 regulates Usp18 gene expression
loss of early protection against footpad sary to promote adaptive immunity. and thus virus replication in CD169+

316 Immunity 36, March 23, 2012 ª2012 Elsevier Inc.

Immunity
Previews
macrophages warrants analysis. Mose-
man et al. (2012) go on to show that B
cell-derived LTa1b2 is critical for inducing
the protective phenotype of the SCS
macrophages. When B cells are the only
cell type that cannot produce LTa1b2,
macrophages are able to capture lymph-
borne viral particles but the virus does
not replicate and type I IFN secretion is
compromised. An outstanding question
is what factors allow virus replication to
proceed—can the effects all be attributed
to the inability of SCS macrophages to
respond to autocrine as well as perhaps
paracrine type I interferon? The study by
Moseman et al. (2012) along with other
available data suggest the fascinating
possibility that the immune system has
evolved to allow a certain proscribed
degree of microbial growth to ‘‘prime the
pump’’ in order to promote both rapid
innate immunity and provide sufficient
antigenic material and inflammatory
signals to promote adaptive immunity to
Natural ‘‘Helper’’ Cells in the Lung:
Good or Bad Help?
Shigeo Koyasu1,2,3,* and Kazuyo Moro1,2,4
1Department of Microbiology and Immunology, Keio University School of Medicine, Tokyo 160-8582, Japan
2Laboratoryfor Immune Cell System, RIKEN Research Center for Allergy and Immunology (RCAI), Kanagawa 230-0045, Japan
3Research Center for Science Systems, Japan Society for the Promotion of Science (JSPS), Tokyo 102-8472, Japan
4Japan Science and Technology Agency (JST), Precursory Research for Embryonic Science and Technology (PRESTO), Tokyo 102-0076,
Japan
*Correspondence: koyasu@z3.keio.jp
DOI 10.1016/j.immuni.2012.03.001
The natural helper (NH) cell comprises a newly identified Th2 cell-type innate lymphocyte population. In this
issue of Immunity, Halim et al. (2012) provide evidence that NH cells reside in the lung and play a critical role in
protease allergen-induced airway inflammation.
Proteases are important components of
many allergens (Reed and Kita, 2004).
For example, papain is a well-known
protease that causes occupational
asthma, and native papain but not heat-
inactivated papain induces lung inflam-
mation in mice. House dust mites also
produce a well-known allergen whose
allergy-inducing ability is largely depen-
dent on its protease activity. In addition,
invasion of host tissues by helminthes
prevent entry of pathogens upon sec-
ondary encounter. In fact, recent findings
indicate that a specialized subset of
dendritic cells are permissive for the initial
replication of Listeria monocytogenes
that leads to the induction of a rapid
innate response leading to the generation
of a protective T cell response (Edelson
et al., 2011). Additional research will be
needed to determine whether events
such as these are more commonplace
than previously appreciated.
REFERENCES
Benedict, C.A., Banks, T.A., Senderowicz, L., Ko,
M., Britt, W.J., Angulo, A., Ghazal, P., and Ware,
C.F. (2001). Immunity 15, 617–626.
Ciavarra, R.P., Taylor, L., Greene, A.R., Yousefieh,
N., Horeth, D., van Rooijen, N., Steel, C., Gregory,
B., Birkenbach, M., and Sekellick, M. (2005).
Virology 342, 177–189.
Delale, T., Paquin, A., Asselin-Paturel, C., Dalod,
M., Brizard, G., Bates, E.E., Kastner, P., Chan, S.,
occurs via high protease activities and
helminth infection induces rapid activa-
tion of Th2 cell-type inflammatory re-
sponses. Proteases are thought to disrupt
mucosal integrity by digesting cell adhe-
sion molecules and further act on
protease-activated receptors to activate
airway epithelial cells. The cytokines
thymic stroma lymphopoietin (TSLP),
IL-25, and IL-33 derived from epithelial
cells activated in this way induce rapid
Immunity 36, March 23, 2012 ª2012 Elsevier Inc. 317
Akira, S., Vicari, A., et al. (2005). J. Immunol. 175,
6723–6732.
Edelson, B.T., Bradstreet, T.R., Hildner, K.,
Carrero, J.A., Frederick, K.E., Kc, W., Belizaire,
R., Aoshi, T., Schreiber, R.D., Miller, M.J., et al.
(2011). Immunity 35, 236–248.
Garcı́a-Sastre, A., and Biron, C.A. (2006). Science
312, 879–882.
Honke, N., Shaabani, N., Cadeddu, G., Sorg, U.R.,
Zhang, D.E., Trilling, M., Klingel, K., Sauter, M.,
Kandolf, R., Gailus, N., et al. (2012). Nat. Immunol.
13, 51–57.
Iannacone, M., Moseman, E.A., Tonti, E., Bosurgi,
L., Junt, T., Henrickson, S.E., Whelan, S.P.,
Guidotti, L.G., and von Andrian, U.H. (2010).
Nature 465, 1079–1083.
Mebius, R.E., Nolte, M.A., and Kraal, G. (2004).
Crit. Rev. Immunol. 24, 449–464.
Moseman, E.A., Iannacone, M., Bosurgi, L., Tonti,
E., Chevrier, N., Tumanov, A., Fu, Y.-X., Hacohen,
N., and von Andrian, U.H. (2012). Immunity 36, this
issue, 415–426.
Schneider, K., Loewendorf, A., De Trez, C., Fulton,
J., Rhode, A., Shumway, H., Ha, S., Patterson, G.,
Pfeffer, K., Nedospasov, S.A., et al. (2008). Cell
Host Microbe 3, 67–76.
Th2 cell-type inflammation. Polymor-
phisms of IL-33 and its receptor ST2 are
associated with allergic diseases,
including asthma in humans, demon-
strating the importance of epithelial cell-
derived cytokines for the onset of Th2
cell-type immune responses.
Papain causes asthma-like symptoms
associated with Th2 cell-type reactions
such as eosinophilia and goblet cell
hyperplasia in Rag-deficient mice. These