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Cutting Edge |
Departments of Medicine and Microbiology, Boston University School of Medicine, and Immunobiology Unit, Evans Memorial Department of Clinical Research, Boston University Medical Center, Boston, MA 02118
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Abstract |
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 Top Abstract IntroductionReferences |
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Introduction |
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TopAbstractIntroductionReferences |
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Beyond phenotype, functional differences between B-1 and B-2 cells are apparent in the signals required for cell cycle progression. B-1 cells fail to enter cell cycle in response to anti-Ig stimulation, which drives B-2 cells into S phase (8). This hyporesponsiveness to sIg engagement may relate to insufficient activation of phospholipase C and/or modulation of signal transduction by CD5-associated SHP-1 phosphatase (9, 10, 11). Conversely, B-1 cells enter S phase in response to treatment with phorbol ester, whereas B-2 cells are stimulated by the combination of a phorbol ester and a calcium ionophore, but not by phorbol ester alone (12). This hyperresponsiveness to phorbol ester stimulation is reflected in the early induction of cyclin D2 expression, and the assembly of active cyclin D2 and cyclin D3 complexes with cdk4/6, neither of which occurs in phorbol ester-treated B-2 cells (13, 14).
In normal individuals B-1 cells are responsible for the majority of nonimmune serum IgM and contribute substantial amounts of resting IgA (15, 16, 17, 18). B-1 cell-derived Ig generally adheres more closely to the germline state than B-2 Ig, as a result of diminished somatic mutation and reduced length of nontemplated N-insertions, and is thus repertoire restricted (19, 20, 21, 22). The B-1 repertoire is selected, as exemplified by overrepresentation of anti-PtC specificities and H chain genes associated with PtC binding (23, 24). B-1 Ig is often found to recognize discrete microbial cell wall determinants (25, 26, 27). This has led to the suggestion that B-1 cells produce natural Ab, representing a set of specificities encoded in the germline and evolutionarily retained that provides (at low affinity) a degree of serological protection against a range of microorganisms prior to the immunization that accompanies microbial pathogenesis. Evidence that natural Ig (and, perhaps, bacterially induced B-1-derived Ig (28)) plays a key role in limiting microbial dissemination and insuring the survival of infected animals has produced a new appreciation of the importance of B-1 cells to the overall scheme of immunity and a renewed emphasis on understanding B-1 cell origin and function (16, 29, 30, 31, 32, 33).
B-1 cells are intriguing in view of their pathophysiological associations with human diseases. B-1 cells have been implicated in the pathogenesis of autoimmunity because 1) increased numbers of B-1 cells are found in patients and animals with some autoimmune dyscrasias (7, 15, 34, 35); 2) elimination of B-1 cells reverses autoimmunity in some situations (36); 3) B-1 cell Ig displays binding to self Ag (37); and 4) B-1 cells can undergo isotype switching and somatic mutation, meaning that B-1 cells can contribute to pathological high-affinity, IgG autoreactive Ab (38, 39). Separately, B-1 cells have been connected with malignant transformation. B-1 cells represent the cell of origin for human chronic lymphocytic leukemia, the malignant B cells of which typically express CD5 (40). In mice, monoclonal expansions of B-1 cells that resemble chronic lymphocytic leukemia develop in almost all individuals with increasing age; furthermore, New Zealand Black mice, which contain increased numbers of B-1 cells, develop several types of B-1-derived lymphomatous malignancies early on (41, 42). These associations with autoimmune and malignant dyscrasias further impel the drive to understand the regulation of B-1 cell development and activity.
Concepts regarding the origin of B-1 cells have changed over the years.
Early work suggested that B-1 cells exist as a separate lineage,
distinct from conventional B cells and T cells (see Fig. 1
). This was based on experiments using B
cell depletion and bone marrow chimeras, which indicated that the
progenitors for B-1 cells are not the same as the progenitors for B-2
cells (5, 43, 44, 45). Additional studies comparing adoptive
repopulation by fetal omentum, fetal liver, and adult bone marrow
precursors demonstrated distinct tissue and developmental specificity
in the location of progenitors for B-1 (fetal omentum and fetal liver)
and B-2 cells (adult bone marrow), strongly supporting the idea of
lineage separation (46, 47, 48). Furthermore, in lethally
irradiated adult recipients rescued by infusion of bone marrow stem
cells, B-1 cell repopulation required concurrent transfer of
sIg+ B-1 cells, again suggesting that the B-1
cell population is distinct, and in the process defining the capacity
of B-1 cells for self-replenishment (44). These and other
results reviewed by Herzenberg et al. (49), including
studies of feedback inhibition, suggest that B-1 cells represent the
end product of a unique lymphoid lineage.
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). This
concept is supported by several interrelated observations: 1)
stimulation of conventional B-2 cells by anti-Ig for 2 or more days
in vitro induces expression of CD5 (50), and these
CD5+ B-2 cells acquire the B-1 characteristic of
PMA responsiveness (51); 2) transgenic expression of
a representative B-1 cell BCR (VH12V
4) in vivo produces a
marked increase in the number of B-1 cells (52); 3)
deficiency of any of several intermediates required for sIg signaling
(Bruton’s tyrosine kinase, phosphatidylinositol-3 kinase, B cell
linker, vav, phospholipase C
2, and protein kinase
C
) results in a substantial reduction in the number and proportion
of B-1 cells (see Ref. 53 for references); and 4) mutation
of inhibitory SHP-1 phosphatase in
mev/mev mice
is associated with increased numbers of B-1 cells (15, 54, 55). These results, reviewed by Wortis and Berland
(53), and other reports concerning sIg density and B cell
development (56, 57), suggest that the nature and quality
of sIg signaling determines B-1 cell differentiation, which can only be
embarked upon after BCR expression.
It is unclear, however, whether these considerations apply equally to
all B-1 cells, as there is good evidence that splenic and peritoneal
B-1 cells behave differently in various experimental situations. In
VH12V4 transgenic mice, the number (and proportion) of splenic B-1
(B-1S) cells is markedly increased over littermate controls, whereas
the number (and proportion) of peritoneal B-1 (B-1P) cells is increased
less dramatically. Thus, the Ig transgene appears to expand the B-1S
cell compartment in preference to the B-1P cell compartment (52, 56). Conversely, in VH12V4.xid mice, the number
and proportion of the more abundant B-1S cells that characterize
VH12V4 mice are diminished to a greater extent than the number and
proportion of B-1P cells; more to the point, all PtC-binding B cells in
the peritoneal cavity are B-1, whereas most of the PtC-binding B cells
in the spleen are B-2 (58). In this situation,
interference with BCR signaling diminishes the B-1S cell compartment in
preference to the B-1P cell compartment. Similarly, in comparing
VH12.BLNK-/- and VH12 mice, the proportion of
splenic lymphocytes that are B-1 cells is diminished to a greater
extent than the proportion of peritoneal lymphocytes that are B-1 cells
(59). In other words, in clearly defined Ig transgenic
situations, the same Ag receptor engagement affects splenic and
peritoneal B-1 cell populations somewhat differently.
This, in turn, suggests that these B-1 cell populations differ, a
notion strongly supported by several lines of evidence: 1) Mac-1
expression is absent on B-1S cells, whereas B-1P cells are
Mac-1+ (60); 2) anti-Ig induces
an increase in intracellular Ca2+ in B-1S cells,
but not in B-1P cells, obtained from VH11V9 anti-PtC Ig
transgenic mice (61); 3) CXCL13 deficiency fails to alter
the number of B-1S cells, whereas the number of B-1P cells is greatly
diminished (62); 4)
anti-Gal
1–3Gal1–4GlcNAc Abs in
1,3-galactosyltransferase-deficient mice are produced exclusively by
B-1S-like B cells and not by B-1P cells, even though B-1 cells that
recognize Gal1–3Gal1–4GlcNAc are present in the peritoneal
cavity (63); 5) nuclear extracts prepared from B-1S and
B-1P cells differ in transcription factor expression (64);
6) RNA analyses indicate differences in gene expression between B-1S
and B-1P cells (Ref. 64 and J. R. Tumang and T.
L. Rothstein, unpublished observations); and 7) B-1S cells fail to
progress in cell cycle in response to PMA, whereas B-1P cells are
strongly stimulated (64). These results indicate that
splenic and peritoneal B-1 cells differ phenotypically, biochemically,
and functionally; the breadth and complexity of the differences thus
far documented raise the possibility that they relate to distinct
origins and/or developmental pathways for these B-1 populations.
Exceptions to the presumed rule that the strength of sIg signaling
directly determines the number of B-1 cells serve to further
deconstruct current paradigms. Notably, Aiolos-deficient mice contain
splenic B cells that express an activated phenotype and are
hyperresponsive to anti-Ig stimulation, yet have markedly
diminished numbers of peritoneal B-1 cells (65).
Conversely, OCA-B-deficient mice contain splenic B cells with markedly
diminished responsiveness to anti-Ig and yet have increased numbers
of peritoneal B-1 cells (66, 67). Thus, in certain
situations, sIg signal strength, at least as gauged by the readout of
cell cycle progression, does not correlate directly with B-1 cell
number. Along the same lines, mice expressing VHB1–8V3–83, which
encodes the Ac146 idiotype, contain Ac146-positive B cells among both
the B-1 and the B-2 populations within the peritoneal cavity
(68), and, as noted above, VH12V4.xid B
cells may be either B-1 or B-2, suggesting that forces other than, or
in addition to, simple Ig binding dictate development along the B-1 or
B-2 pathways. The notion that B-1 and B-2 cells respond differently to
such forces is strongly supported by recent reports that deficiencies
of BLyS (BAFF, TALL-1, THANK, zTNF4) and IL-7 are associated
with marked reductions in B-2 but not B-1 cells (69, 70).
In addition, knockout of cyclin D2 results in the loss of B-1 cells
without perturbing B-2 cell development, suggesting the possibility
that mature B-1 cell populations result from marked expansion of
relatively few precursors and raising the possibility that sIg
signaling serves as much to trigger B-1 cell expansion (and/or
maintenance; see Ref. 59) as to initiate B-1 cell
differentiation (71). Lack of expansion rather than
differentiation may account for the loss of SM6C10 transgene-positive
B-1 cells in the absence of specific Ag (thy-1)
(72).
The issues raised herein have led us to speculate that all B-1 cells
are produced as a result of sIg signaling (that is involved either in
differentiation or expansion or maintenance), but that sIg signaling is
perceived differently by precursors destined to become B-1P cells vs
precursors destined to become B-1S cells, and depends to a greater or
lesser extent on the presence of various nuclear factors that influence
transcription and the response to sIg engagement (see Fig. 2). Less anthropomorphically, we
speculate that the sIg signaling threshold required to trigger B-1 cell
differentiation/expansion is higher for precursors that ultimately
become B-1S cells than for precursors that ultimately become B-1P
cells, explaining why increases (e.g., VH12V4) and decreases (e.g.,
VH12V4.xid) in BCR signaling strength appear to affect
the splenic B-1 cell population more dramatically than the peritoneal
B-1 cell population, and why some BCRs produce B-1P cells but not B-1S
cells (72). We further suggest that, following
differentiation to B-1 cell status, CD5 regulates (inhibits) sIg
signaling, as pointed out by Bondada and colleagues (10, 11), explaining why peritoneal B-1 cells that presumably
had a low threshold for sIg signaling as precursors fail to respond to
anti-Ig following differentiation (8, 10, 11, 12, 73). In
theory, at one extreme, the threshold for peritoneum-directed B-1 cells
could be zero, in which case this scheme would reduce to something akin
to the classical lineage hypothesis, with some precursors destined to
become B-1 cells, but B-1 cell development from other precursors
dependent on sIg signaling. Alternatively, at the other theoretical
extreme, the threshold for peritoneum-directed B-1 cells could be more
or less the same as for spleen-directed B-1 cells, in which case this
scheme would reduce to the current differentiation hypothesis in which
the strength of the interaction between ligand and BCR determines B-1
cell development for all B cell precursors. Most likely, the threshold
for peritoneum-directed B-1 cells is more than zero but less than the
threshold for spleen-directed B-1 cells.
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Much of this new construction is based on the observation that splenic
and peritoneal B-1 cells differ one from another. It is therefore
important to note that our data, in particular, have been generated by
comparing VH12V4 Ig transgenic B-1S cells with normal BALB/c B-1P
cells because of the difficulty in obtaining sufficient numbers of
normal B-1S cells to prepare nuclear extracts and RNA for subsequent
analysis. It is thus possible that differences between B-1S and B-1P
cells are attributable to differences between transgenic and normal
B-1S cells, rather than differences between B-1S and B-1P cells, if
normal B-1S and normal B-1P cells are, in fact, alike. This is not an
unreasonable hypothesis because 1) Ig transgenic B cells cannot
experience early steps of pre-BCR expression and putative selection in
the same way as normal B cells do, and thus may develop abnormally; and
2) the naturally occurring VH12 transgene (C.B17-derived,
IgHb) has been reported to encode a high-affinity
PtC receptor that may produce particularly elevated B cell expansion
(and it is notable in this context that the spleens of VH12V4 mice
are often enlarged and contain supernormal numbers of B cells)
(49). In contrast, VH12V4 B-1S cells are in all
phenotypic respects the same as normal B-1S cells (52).
Although the possibility that the non-B-1P-like characteristics of
VH12V4 B-1S cells are peculiar to VH12V4 might seem to represent
an uninteresting outcome, it could have important implications for
concepts of B-1 cell differentiation based on such transgenic
models.
Previous work makes clear that there is not always a direct relationship between the magnitude of sIg signaling (as judged by proliferation) and the number of B-1 cells (see above). The same is true of splenic and peritoneal B-1 cell development; not all alterations in sIg signaling affect B-1S and B-1P cells differently. In studies of coreceptor deletion, loss of CD22 or CD19 diminished sIg-induced proliferation but produced either little change or similar reductions in the number of B-1S and B-1P cells (79, 80). However, such studies can be difficult to interpret. CD22 deletion produces both positive and negative effects on B cell activation, and native CD19 levels differ for B-1S and B-1P cells. Moreover, the effects of genetic lesions on sIg signaling in mature B-2 cells may not accurately reflect the outcomes of sIg engagement during earlier B cell stages that ultimately determine the magnitude of B-1 cell development and/or expansion. Of note, the important and key role for specific sIg signaling thresholds in the production of splenic and peritoneal B-1 cells is not meant to exclude a role for other endogenous or exogenous factors that may affect development. Such factors may be responsible for differences between mature B-1S and B-1P cells once sIg signaling thresholds have been exceeded and B-1 cell production has been initiated.
B cell precursors and developing B cells that experience strong BCR
signaling may yet follow any one of several alternatives to the B-1
pathway (see Fig. 2). These include receptor editing, apoptotic
deletion, and tolerance induction (81, 82, 83). The latter is
especially intriguing because, like B-1 cells, tolerant B cells fail to
respond to anti-Ig and because, like B-1 cells, tolerant B cells
express CD5 (albeit at relatively low levels) (84). The
precise relationship among the mechanisms responsible for these various
B cell fates is presently unknown but is presumably of key importance,
because, alone among the outcomes discussed above, B-1 cells
constitutively produce autoreactive natural Ig, whereas
receptor-edited, apoptotic, and tolerant B-2 cells do not. Thus,
understanding the means by which self-reactive B cell precursors are
directed to the B-1 cell pool, be it affinity, location, timing,
coreceptor expression, nature of the Ag, or nature of the B cell, is
likely to shed light on the normal process by which natural Ig is
generated, and may illuminate mechanisms that underlie or exacerbate
autoimmune dyscrasias and that promote dysregulated neoplastic
expansion. Furthermore, it is important to understand the mechanisms
that produce splenic as opposed to peritoneal B-1 cells, because B-1S
cells appear functionally and biochemically different from B-1P cells
in terms of responsiveness to sIg engagement and thus may express some
adaptive characteristics. A full understanding of B-1 cell features,
behavior, and function is likely to come about only by examining the
differentiative processes that produce B-1 and B-2 cells, and that
produce distinct splenic and peritoneal B-1 cell populations.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Thomas L. Rothstein, Immunobiology Unit, Evans Biomedical Research Center, Room 437, Boston Medical Center, 650 Albany Street, Boston, MA 02118. E-mail address: trothstein{at}medicine.bu.edu
3 Abbreviations used in this paper: sIg, surface Ig; BCR, B cell receptor; PtC, phosphatidyl choline; B-1P, peritoneal B-1; B-1S, splenic B-1.
Received for publication January 3, 2002. Accepted for publication March 5, 2002.
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2 in B-1 lymphocytes. Int. Immunol. 6:1011. transgenic mice are derived from B-1 (Ly-1 B) cells. Int. Immunol. 5:1317.9 B cell antigen receptor drives generation of CD5+ B cells both in vivo and in vitro. J. Immunol. 164:4586.1,3Gal epitopes in 1,3-galactosyltransferase-deficient mice. J. Immunol. 165:5518.This article has been cited by other articles:
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