Multiple Regulatory Mechanisms Control B-1 B Cell Activation

Abstract

B-1 cells constitute a unique subset of B cells identified in several species including mice and humans. B-1 cells are further subdivided into B-1a and B-1b subsets as the former but not the later express CD5. The B-1a subset contributes to innate type of immune responses while the B-1b B cell subset contributes to adaptive responses. B-1 cell responses to B cell receptor (BCR) as well as Toll-like receptor (TLR) ligation are tightly regulated due to the cross-reactivity of antigen specific receptors on B-1 cells to self-antigens. B-1 cells are elevated in several autoimmune diseases. CD5 plays a major role in down regulation of BCR responses in the B-1a cell subset. Reduced amplification of BCR induced signals via CD19 and autoregulation of BCR and TLR responses by B-1 cell produced IL-10 appear to have a role in regulation of both B-1a and B-1b B cell responses. Siglec G receptors and Lyn kinase also regulate B-1 cell responses but their differential role in the two B-1 cell subsets is unknown.

Full text

MINI REVIEW ARTICLE
published: 17 December 2012
doi: 10.3389/fimmu.2012.00372
Multiple regulatory mechanisms control B-1 B cell
activation
Vishal J. Sindhava1†and Subbarao Bondada1,2*
1Department of Microbiology, Immunology and Molecular Genetics, University of Kentucky College of Medicine, Lexington, KY, USA
2Markey Cancer Center, University of Kentucky College of Medicine, Lexington, KY, USA
Edited by:
Thomas L. Rothstein,The Feinstein
Institute for Medical Research, USA
Reviewed by:
Louis Justement, University of
Alabama at Birmingham, USA
Masaki Hikida, Kyoto University,
Japan
*Correspondence:
Subbarao Bondada, Department of
Microbiology, Immunology and
Molecular Genetics, University of
Kentucky College of Medicine, 303
Combs Cancer Building, Lexington,
KY 40536-0096, USA.
e-mail: bondada@uky.edu
†Present address:
Vishal J. Sindhava, Department of
Pathology and Laboratory Medicine,
University of Pennsylvania,
Philadelphia, PA 19104, USA.
B-1 cells constitute a unique subset of B cells identified in several species including mice
and humans. B-1 cells are further subdivided into B-1a and B-1b subsets as the former but
not the later express CD5.The B-1a subset contributes to innate type of immune responses
while the B-1b B cell subset contributes to adaptive responses. B-1 cell responses to B
cell receptor (BCR) as well as Toll-like receptor (TLR) ligation are tightly regulated due to
the cross-reactivity of antigen specific receptors on B-1 cells to self-antigens. B-1 cells are
elevated in several autoimmune diseases. CD5 plays a major role in down regulation of
BCR responses in the B-1a cell subset. Reduced amplification of BCR induced signals via
CD19 and autoregulation of BCR and TLR responses by B-1 cell produced IL-10 appear to
have a role in regulation of both B-1a and B-1b B cell responses. Siglec G receptors and
Lyn kinase also regulate B-1 cell responses but their differential role in the two B-1 cell
subsets is unknown.
Keywords: B lymphocyte, B-1 cell, B cell receptor,Toll-like receptor, CD5, SHP-1, CD19, IL-10
INTRODUCTION
B cells are heterogeneous in their surface phenotypes, anatomical
localization, capacity for self-renewal, and functional properties.
The two major subsets of the B cells are B-2 and B-1 B cells, which
were initially defined by differential expression of a classical T cell
specific differentiation antigen, CD5 (expressed on B-1 cells). The
B cell receptors (BCRs) on B-1 cells exhibit polyreactivity enabling
them to respond to conserved epitopes on microbes, but that also
leads to cross-reactivity with self-antigens. In this review we sum-
marize the mechanisms involvedin regulation of BCR and Toll-like
receptor (TLR) mediated B-1 cell activation.
B-2 CELLS
B-2 cells are produced in bone marrow from hematopoietic stem
cells and migrate to secondary lymphoid organs as immature B
cells. Transitional B cells are the most immature B cells in the
spleen and are the crucial link between bone marrow immature
and peripheral mature B cells (Chung et al., 2003). These tran-
sitional B cells are called the T1 subset when they first emerge
from bone marrow, which mature into T2 subset mainly in the
spleen. The T1 subset is a stage of negative selection against
self-reactive B cells that have escaped central tolerance mech-
anisms in the bone marrow (Cancro et al., 1998). The T2 B
cells further mature and differentiate into follicular and mar-
ginal zone B cells (Miller et al., 2006). B cell-activating factor,
BAFF (a.k.a. B Lymphocyte Stimulator, BLyS) is essential for
the survival of mature follicular and marginal zone B cells. In
both BAFF receptor mutant and BAFF knockout mice, most
transitional B cells fail to differentiate into follicular B cells, and
the few follicular B cells formed have a short lifespan (Lentz
et al., 1996;Gross et al., 2001;Schiemann et al., 2001;Gavin
et al., 2005). BAFF signaling mainly promotes B cell survival,
as enforced expression of anti-apoptotic factors Bcl-2 or Bcl-xL
restored splenic B lymphocyte development in BAFF-R mutant
mice (Amanna et al., 2003;Tardivel et al., 2004). Upon exposure
to antigen, follicular B cells undergo clonal expansion, Ig class
switching, and differentiation into plasma and memory B cells
(McHeyzer-Williams and McHeyzer-Williams, 2005). The tran-
sitional, follicular, and marginal zone B cells comprise the B-2
subset.
B-1 CELLS
B-1 cells were first identified on the basis of expression of CD5,
a pan T cell marker, on a subset of B cells (Manohar et al., 1982;
Hayakawa et al., 1983). B-1 cells are mainly present in peritoneal
cavities, pleural cavities, and various parts of intestine and con-
stitute only a small fraction of B cells in the spleen (Kroese et al.,
1992). B-1 cell origin and development occurs primarily during
fetal and perinatal life. There have been two different models pro-
posed for the origin of the B-1 cells, lineage model, and selection
model. The lineage model supports the existence of distinct prog-
enitors for B-1 and B-2 cells (Hardy and Hayakawa, 1991;Kantor
et al., 1992;Herzenberg and Tung, 2006). Thus transfer of fetal
liver cells reconstituted both B-1 and B-2 cell populations,whereas
adult bone marrow transfer reconstituted conventional B (B-2)
cells but not B-1 cells. In contrast, the selection model proposes a
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Sindhava and Bondada B-1 B cell regulation
common progenitor for both B-1 and B-2 cells and antigen selec-
tion (antigenic stimuli) determines the development of B cells
with B-1 or B-2 characteristics (Lam and Rajewsky, 1999;Berland
and Wortis, 2002). Studies showing that CD5 expression can be
induced by BCR signaling in the presence of certain cytokines and
BCRs specific to some antigens support antigen selection mod-
els. Lam and Rajewsky (1999) showed that co-expression of non
B-1 specific BCR (VHB-1-8 or VHglD42) along with B-1 specific
BCR (VH12) on B cells leads to development of B-2 but not B-
1 cells. They proposed that expression of non B-1 specific BCR
dilutes out VH12-containing BCR complexes on the cell surface
and presumably acts in a “dominant-negative” manner and may
not provide sufficient signals for the development of B-1 phe-
notype. This can perhaps best be explained by postulating that
signaling via a BCR of a certain specificity, expressed at the cell
surface at high density, is required to drive the differentiation
of B cells into the B-1 subset (Lam and Rajewsky, 1999). Both
the models are well supported by evidence and are the subject
of considerable debate. However, a recent study from Dorshkind
and colleagues identified specific B-1 cell restricted progenitors
(Lin−CD45Rlo-negCD19+cells) in bone marrow, which prefer-
entially reconstituted functional B-1 B cells, but not B-2 B cells,
in vivo, providing strong support to the lineage model (Montecino-
Rodriguez et al., 2006). Moreover,using single hematopoietic stem
cells for reconstitution Ghosn et al. (2012) demonstrated that B-1a
cell lineage derives from a precursor that is distinct from other B
cell lineages.
B-1 CELL SUBSETS
Along with the presence of CD5 on the surface, B-1 cells are further
differentiated from B-2 cells by surface expression of CD11b (Mac-
1), high levels of IgM, and low levels of IgD (Tung et al., 2004).
B-1 cells are subdivided into three different subsets, B-1a, B-1b,
and B-1c, on the basis of CD5 and CD11b expression. B-1a cells
are CD11b+CD5+, B-1b cells are CD11b+CD5−, and the newly
described rare subpopulation of B-1c cells is CD11b−CD5+(Tung
et al., 2004;Hastings et al., 2006). B-1a cells have a role in innate
immunity via their contribution to natural antibodies, while B-
1b cells are critical in development of IgM memory cells (Berland
and Wortis, 2002). The functional properties of B-1c are essentially
similar to those of B-1a and B-1b B cells (Hastings et al., 2006). The
unique markers for B-1 cells in the human were unclear since CD5
was expressed by activated human B cells. More recently, Griffin
et al. (2011) have characterized human B-1 cell surface phenotype
and function, which resembled the properties of murine B-1 cells
very closely (Griffin et al., 2011;Griffin and Rothstein, 2012).
B-1 cells are important in protection against certain bacterial
infections such as S. pneumoniae,Borrelia hermsii as well as in the
early IgM response against viruses such as influenza (Baumgarth
et al., 2000;Alugupalli et al., 2003;Haas et al., 2005). Despite their
role in protection against infection, B-1 cell antibodies have been
found to be poly-reactive and as such are reactive to self-antigens
such as those on red blood cells, thy 1.2, single stranded DNA
(Berland and Wortis, 2002). Moreover, B-1 cells have been found
to be elevated in autoimmune diseases both in mouse and human.
In mouse models, elimination of B-1 cells by genetic deficiency
reduced autoimmunity (Duan and Morel, 2006).
BCR SIGNALING IN B-1 CELLS
B cell receptor signaling plays a critical role in B-1 cell devel-
opment, survival, or expansion. Transgenic mice or mice with
mutations that disrupt BCR signaling have a decrease in B-1 cell
numbers, and mutations that enhance BCR signaling result in
increased B-1 cell compartment (Berland and Wortis, 2002). How-
ever, the cross-reactivity of B-1 BCRs with self-antigens raised
the question of how B-1 cells are prevented from activation via
self-antigens in the absence of overt infection. Studies of BCR sig-
naling have demonstrated distinct differences between B-1 and
B-2 cells. Engagement of BCR on B-2 cells leads to robust intra-
cellular calcium mobilization and proliferation, while in B-1 cells,
BCR ligation induces modest calcium mobilization, little or no
proliferation, and increased apoptosis (Murakami et al., 1992;
Morris and Rothstein, 1993;Bikah et al., 1996;Sen et al., 1999).
Here we summarized the key molecules that negatively regulate
BCR and TLR signaling in B-1 cells and have a role in B-1 cell
hypo-responsiveness to BCR ligation.
Negative regulatory role of CD5 in B-1a cells
CD5 is a 67-kDa monomeric type 1 transmembrane glycoprotein,
historically also known as Lyt-1 or Ly-1. Extracellular domains
of CD5 are characterized by the presence of the highly conserved
scavenger receptor cysteine-rich domain. CD5 expression was first
identified on T cells (Boyse et al., 1968) and subsequently shown
to be expressed on B cells (Manohar et al., 1982;Okumura et al.,
1982;Hardy et al., 1983;Hayakawa et al., 1983). CD5+B cells,
later termed B-1a cells, have unique function of “spontaneous”
IgM secretion that contributes to natural antibodies (Hayakawa
et al., 1983). Also, B-1 cells have a limited BCR repertoire with
dominant cross-reactivity to self-antigens, but expansion of these
poly-reactive B-1 cells is limited (Berland and Wortis, 2002). This
limited expansion of self-reactive B-1 cells may be in part due to
the presence of various mechanisms that negatively regulate BCR
signaling.
Various studies identified CD5 as one of the negative regulators
of BCR signaling, similar to its ability to inhibit T cell function
(Tarakhovsky et al., 1995). In B cells CD5 associates with mIgM
upon BCR stimulation (Lankester et al., 1994). However, CD5 is
shown to be constitutively associated with mIgM in peritoneal B-1
cells (Sen et al., 1999). Bikah et al. (1996) demonstrated for the first
time that CD5 negatively regulates BCR signaling in peritoneal B-1
cells. B-1 cells from both wild type (WT) and CD5 KO mice pro-
liferated comparably in response to anti-CD40 and LPS. However,
only CD5 KO B-1 cells, but not WT B-1 cells, proliferated to anti-
IgM stimulation. This involved sustained calcium mobilization
and increased nuclear localization of NF-κB following BCR liga-
tion in CD5 KO compared to WT peritoneal B-1 cells. Additionally,
blocking of CD5 association with mIgM rescued the proliferative
defect of B-1 cells upon BCR ligation (Bikah et al., 1996). Using a
novel fusion protein containing the extracellular and transmem-
brane domains of FcγRIIB and the cytoplasmic region of CD5
Gary-Gouy et al. (2000, 2002) showed that co-cross-linking of
BCR with the chimeric protein induced tyrosine phosphoryla-
tion in CD5 cytoplasmic tail along with rapid inhibition of BCR
induced calcium transients and extracellular regulated kinase-2
(ERK2) activation. Subsequent they showed that Y429, residue
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Sindhava and Bondada B-1 B cell regulation
outside the putative immune receptor tyrosine based inhibitory
motif (ITIM) of CD5 cytoplasmic domain is responsible for the
inhibition of BCR induced calcium response, Akt relocalization
(Gary-Gouy et al., 2002), activation of the Ras/ERK2 pathway as
well as IL-2 production (Gary-Gouy et al., 2002).
Using the well-known transgenic mouse model of anti-hen
egg lysozyme (HEL) crossed to transgenic mice expressing sol-
uble HEL (Goodnow et al., 1988), Hippen and Behrens showed
that anergic B cells expressed significant surface levels of CD5,
though lower than those expressed on typical B-1a cells. This
suggested that a low level of CD5 induction on B cells upon stim-
ulation through auto-antigen might be sufficient to induce an
anergic state in self-reactive B cells and thus limiting production
of autoantibodies. Consistent with such a concept, CD5 KO mice,
but not CD5+mice, that are transgenic for both HEL specific BCR
and soluble lysozyme produced antibody to the self-antigen, HEL
(Hippen et al., 2000). Also, the CD5 KO HEL specific B cells that
are no longer anergic showed enhanced proliferative responses
and calcium mobilization upon BCR ligation. Together, data from
Bikah et al. (1996) and by Hippen et al. (2000) suggested that CD5
negatively regulates BCR signaling and limits self-reactive B cell
responses. Similar to anergic B cells in the transgenic model, con-
stitutive expression of CD5 on B-1a cells might also play a role in
limiting the expansion of auto-reactive B-1a cells.
Lyn, SHP-1, CD22 and Siglec G
B cell receptor signal transduction occurs via activation of sev-
eral protein tyrosine kinases (PTK), including members of the Src
family kinases (SFKs; Cambier et al., 1994). In addition to taking
part in activation of the BCR signaling, Lyn, an SFK, negatively
regulates BCR signaling by phosphorylating the ITIM motifs in
B cell co-receptors (DeFranco et al., 1998). Phosphorylation of
ITIM motif with Lyn induces the recruitment of negative mole-
cular switches, like protein tyrosine phosphatases (PTP; Thomas,
1995). Dasu et al. (2009) also made the surprising observation that
B-1 cells have a constitutively active Lyn. Lyn appears to have dual
roles in B-1 cells such that high doses provide negative signals,
whereas small amounts of Lyn were essential for B-1 cell activa-
tion as demonstrated by rescue of both proliferation and calcium
responses at low doses of Lyn kinase inhibitors (Dasu et al., 2009).
Several PTPs like, tyrosine-protein phosphatase non-receptor
type 6 (SHP-1/PTPN6), SHP-2, and inositol polyphosphate 50
phosphatase are involved in the inhibition of BCR signaling
(Thomas, 1995;Long, 1999). In B cells, SHP-1 associates with
inhibitory receptors like FcR, CD22, and paired Ig-like receptor,
PIR-B (Doody et al., 1995;Pani et al., 1995;Long, 1999). Mothe-
aten and the viable motheaten mice with mutations in the SHP-1
enzyme exhibit autoimmunity and accelerated mortality due to
the presence of hyper-responsive B-1 cells (Cyster and Goodnow,
1995). Moreover, B cell specific deletion of SHP-1 leads to an
expansion of B-1 cells, rescue of BCR induced calcium response
and autoimmunity characterized by anti-DNA antibodies (Pao
et al., 2007).
Cytoplasmic domain of CD5 contains an amino acid sequence
(LAY378KKL), with excellent homology to ITIMs of inhibitory
receptors (Perez-Villar et al., 1999) and thus can interact with SHP-
1. There is a constitutive association of the BCR with SHP-1 in both
B-1 and B-2 cells (Sen et al., 1999). Upon BCR ligation association
of SHP-1 is decreased in splenic B-2 cells, but not in peritoneal B-1
cells. The persistent BCR-SHP-1 association is mediated by CD5 in
peritoneal B-1 cells and is lost in CD5 KO peritoneal B-1 cells or in
wild type B-1 cells when CD5 is sequestered away from BCR (Sen
et al., 1999). These data suggest that CD5 may negatively regulate
BCR-mediated growth signals by recruiting SHP-1 into the BCR
complex in B-1 cells.
The B cell surface molecules CD22 and CD72 can also asso-
ciate with SHP-1, but were not found to have a critical role in
the anergic state of B-1 cells (Ochi and Watanabe, 2000;Lajau-
nias et al., 2002). However, Siglec G, another member of the
CD22 family of sialic acid binding proteins, is important for both
B-1 cell development and for regulating BCR induced calcium
responses, but not BCR induced B-1 cell proliferation (Hoffmann
et al., 2007). Interestingly, CD22−/−Siglec G−/−double knock-
out mice had even greater elevation of BCR induced calcium
responses in B-1 cells suggesting a role for both molecules in regu-
lating BCR responses in B-1 cells (Jellusova et al., 2010a,b). These
double knockouts develop anti-nuclear antibodies and glomerular
nephritis (Jellusova et al., 2010b).
CD19
The inability of B-1a cells to respond well to BCR signaling with a
role for negative regulation by CD5 and SHP-1 is described above.
B-1b B cells, which are CD5 negative by definition, are equally
defective in proliferation induced by BCR cross-linking raising
the possibility that additional mechanisms may exist to down-
regulate BCR responses in B-1 cells (Sen et al., 1999). CD19, a
co-receptor expressed by all B cell subsets, serves as a positive
regulator of BCR signaling and is critical for B cell development
and activation (Cambier et al., 1994;Tedder et al., 1994). CD19
is shown to be involved in the development and self-renewal of
B-1 cells (Krop et al., 1996;Sato et al., 1996). Signals from CD19
and BCR act in synergy to induce robust calcium mobilization in
splenic B-2 cells (Carter et al., 1991;Fujimoto et al., 2001). Using
this criterion, Sen et al. (2002) found that both B-1a and B-1b
B cells are equally hypo-responsive to synergistic calcium mobi-
lization obtained by co-cross-linking BCR and CD19 compared
to B-2 cells. CD19 cross-linking amplifies BCR signaling in part
by recruitment of Vav, a guanine nucleotide exchange factor for
the Rho, Rac, and Cdc42 family of small GTPases (O’Rourke et al.,
1998). Vav binds to phosphorylated tyrosine-391 of CD19 to medi-
ate a sustained increase in intracellular Ca2+concentration and
activation of the mitogen-activated protein kinase, JNK (O’Rourke
et al., 1998). Association of CD19 with Vav is reduced in B-1 cells
(Sen et al., 2002). Similarly BCR dependent proliferation as well as
CD19 mediated augmentation of BCR induced calcium elevation
were deficient in B-1a and B-1b B cell subsets from both spleen
and peritoneal cavity (Dasu et al., 2009). The defects in calcium
response were mainly in the mobilization of extracellular calcium
by both B-1a and B-1b B cells stimulated via CD19 and BCR.
IL-10 AND TLR SIGNALING IN B-1 CELLS
Toll-like receptors are pattern recognition receptors that recognize
pathogen-associated molecular patterns. So far eleven functional
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Sindhava and Bondada B-1 B cell regulation
TLRs (TLR8 and TLR10 genes do not encode functional pro-
teins) have been described in the mouse (Browne, 2012). Several
B cell subsets express TLRs and can be activated via TLR ligands
that result in robust proliferation and antibody secretion, even
in the absence of dendritic cell or T cell help (Genestier et al.,
2007;Gururajan et al., 2007). TLR mediated signals synergize
with self-antigen-mediated BCR signals to stimulate activation
of self-reactive B cells (Leadbetter et al., 2002), and B cell acti-
vation was severely reduced when the mice were deficient in
TLR signaling (Leadbetter et al., 2002;Browne, 2012). B-1 cells
express various TLRs (TLR1, 2, 3, 4, 7, 8, and 9; Gururajan et al.,
2007). B-1 cells are more prone to terminal plasma cell differ-
entiation than B-2 cells upon TLR stimulation (Genestier et al.,
2007). B-1 cell activation and B-1 cell mediated auto-antibody
production are augmented upon stimulation via TLR4 or TLR9
(Murakami et al., 1994;Kubo et al., 2009). Also, TLR signaling
in B-1 cells plays an important role in the clearance of various
pathogens such as influenza virus, pneumococcus, and Borre-
lia spp. (Baumgarth et al., 2000;Alugupalli et al., 2003;Haas
et al., 2005). Sindhava et al. (2010) showed that peritoneal B-1
cells are hypo-responsive to various TLR ligands compared to B-2
cells.
Peritoneal B-1 cells were the first B cell subset to be reported as
being high IL-10 producers (O’Garra et al., 1992). Recently human
CD11b+B-1 cells were also found to spontaneously secrete IL-
10 (Griffin and Rothstein, 2012). IL-10 is a potent regulator of
immune function through its ability to inhibit antigen presenta-
tion, pro-inflammatory cytokine production, T cell proliferation,
and acts as a key effector molecule for certain types of regulatory
T and B cells. As such, IL-10 production by B-1 cells raises the
possibility that B-1 cells may regulate their own function and/or
the function of other immunocompetent cells. Sindhava et al.
(2010) showed that among different B cell subsets from spleen
and peritoneum, B-1 cells from the peritoneum are the major IL-
10 producers. Peritoneal B-1a cells produced highest level of IL-10
followed by B-1b cells, whereas IL-10 production by peritoneal B-2
cells was minimal both constitutively and upon TLR stimulation
(Sindhava et al., 2010). The high levels of IL-10 produced by peri-
toneal B-1 cells regulated the TLR as well as BCR (Sindhava et al.,
unpublished results) induced B-1 cell proliferation in an autocrine
fashion, as B-1 cells from IL-10 knockout mice proliferated signif-
icantly more than WT B-1 cells both in vitro and in vivo. IL-10
regulated B-1 cell response to TLR by inhibiting classical NF-κB
signaling. Furthermore, IL-10 produced by peritoneal B-1 cells
FIGURE 1 | Regulation of B-1 B cell activation. (1 and 2) CD5 mediated
regulation – CD5 acts as an anchor for SHP-1 recruitment on cell surface
near BCR signaling complex, which in turn inhibits BCR signaling. (3)
CD19 mediated regulation – B-1 cells have defective Vav recruitment to
CD19 leading to reduced Ca2+mobilization and cell activation upon BCR
co-stimulation. (4) Src family kinase mediated regulation – Src family
kinase, Lyn, plays an essential role in phosphorylation of CD5 and
subsequent recruitment of SHP-1 on CD5. (5) IL-10 mediated
regulation – B-1 cells make high levels of IL-10 uponTLR and BCR
stimulation, which work in an autocrine manner and inhibit B-1 cell
responses by blocking degradation of IκBαand RelA translocation to the
nucleus.
Frontiers in Immunology | B Cell Biology December 2012 | Volume 3 | Article 372 | 4

Sindhava and Bondada B-1 B cell regulation
limits the clearance of B. hermsii infection (Sindhava et al., 2010).
Thus, similar to BCR signaling, TLR signaling is also regulated in
peritoneal B-1 cells, which might prevent excessive activation of
self-reactive B cells via TLR stimulation.
CONCLUDING REMARKS
B-1 cells express poly-reactive BCRs with cross-reactivity to self-
antigens. Accidental activation by self-antigens is prevented by
multiple mechanisms that keep B-1 cells in anergic state. Lyn, a
major negative regulator of BCR signaling phosphorylates ITIMs
on inhibitory receptors (CD5, Siglecs, etc.) leading to recruitment
of PTPs, which antagonize the BCR mediated activation of PTKs.
Anatomical location of B-1 cells makes them prone to activation
through microbial TLR ligands that might result in auto-antibody
production. IL-10 mediated autoregulation plays a key role in con-
trolling expansion of self-reactive B-1 cells. However, signals from
CD40 and high dose TLR ligands can overcome the anergic state
of B-1 cells enabling their activation during infection. Defects in
the negative regulatory mechanisms may account for elevation of
B-1 cells and autoantibodies in lupus like autoimmune diseases.
Various molecules that negatively regulate B-1 cell activation are
summarized in Figure 1.
ACKNOWLEDGMENTS
This work was supported in part by NIH grants AI21490, AG05731,
CA09357, and AI076956,a grant from Vice President for Research,
University of Kentucky and a grant from Edward P. Evans Founda-
tion to Subbarao Bondada. The authors acknowledge the contri-
butions of Drs. G. Bikah, C. Venkataraman, G. Sen, R. L. Chelvara-
jan, Hsin-Jung Wu, Murali Gururajan, and T. Dasu who were pre-
vious members of the laboratory. Also, the authors acknowledge
Dr. M. E. Woodman and Dr. B. Stevenson for their contributions.
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Conflict of Interest Statement: The
authors declare that the research was
conducted in the absence of any com-
mercial or financial relationships that
could be construed as a potential con-
flict of interest.
Received: 29 September 2012; accepted:
21 November 2012; published online: 17
December 2012.
Citation: Sindhava VJ and Bon-
dada S (2012) Multiple regulatory
mechanisms control B-1 B cell acti-
vation. Front. Immun. 3:372. doi:
10.3389/fimmu.2012.00372
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B Cell Biology, a specialty of Frontiers in
Immunology.
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