By
From the Departments of Microbiology and Immunology, University of Washington, Seattle, Washington 98195
Cells within the DC lineage of white blood cells are the
sentinels of the immune system, the most potent of
APCs; at various ports of entry, they specialize in capturing
antigens and stimulating T cell-associated immunity (1).
DCs regulate the activation of T cells not only by efficiently processing and presenting immunogenic peptides in
association with self-MHC (1), but also via expression of
coreceptor molecules such as CD80 and CD86 (5) and
the production of cytokines such as IL-12 (8).
Although a role for DCs in the activation of T cells is well
established, it is less clear to what extent DCs regulate other cells. It is known that DCs are essential for the development of antibody responses (12), but this has been thought
to be simply a secondary consequence of the requirement
for DCs to activate naive helper T cells. Now several recent findings suggest that DCs may directly regulate B cell
maturation. In this issue of the Journal of Experimental Medicine Dubois et al. (16) report that small numbers (250-1,000
cells) of highly purified CD1a+ dendritic-Langerhans cells
(D-Lc) can directly stimulate activated B cells both to proliferate and produce significant amounts of IgM or IgG. This
dramatic effect is dependent on the B cells being stimulated
through CD40 receptors. Of the B cell populations tested, IgG- and IgA-producing memory B cells are the most responsive to D-Lcs, but IgD+ B cells can also be stimulated
by DCs to produce IgM in vitro.
How might DCs directly induce B cell maturation? DCs
and B cells both constitutively express CD40 and class II,
and both, in response to certain cytokines, LPS or CD40 ligation, upregulate surface CD54 (ICAM-1), CD80, and
CD86 (4, 7, 10, 17). And both DCs and B cells can engage T cells in reciprocal dialogues (19), during which both
the T cell and APC are activated via either cell-cell interaction molecules or locally secreted cytokines. Thus, it is
likely that some type of reciprocal signaling also occurs between DCs and B cells.
Although the DC-dependent B cell proliferation described by Dubois et al. (16) could be mediated by a soluble
factor, optimal induction of antibody production by DCs
required both cell-cell contact, soluble factors, and activation of DCs via their CD40 receptors. Stimulation via
CD40 has a number of effects on DCs including preventing them from dying (20); so one possibility is that some
kind of rescue signal may be required to keep DCs alive in
long-term 15-d cultures with B cells. CD40 ligation also induces DCs (and B cells) to express functional CD40L
(21), and CD40L+ DCs can stimulate B cells directly to secrete IgG and IgA via a CD40L-dependent pathway (21).
Thus, some or all of the cell-cell contact requirement for
DC-dependent antibody production may be mediated by
CD40L-CD40 signaling. The fact that DCs and B cells can
be seen clustered in close contact (16) suggests that as much
remains to be learned about DC-B cell and DC-T-B interactions as remained for DC-T interactions after DCs and T
cells were first found clustered together (12). One intriguing possibility is that B cells in close proximity with
DCs may compete for signals from T cells (such as CD40L)
and thereby influence the type or degree of cytokines made
by DCs (22).
Relatively little is known about the range of cytokines or
chemokines made by cells in the DC lineage, let alone
which of them may regulate B cells. Although IL-12 is secreted by DCs after CD40 ligation (9, 10), it probably has
no direct effect on resting or activated B cells, which do
not express IL-12 receptors (23). DCs or DC-related cell
lines have been reported to make IL-1, IL-6, and TNF- The recent in vitro studies of DC-B cell interactions
(16, 21) leave unanswered a critical question: Where might
a DC stimulate a B cell in vivo? Dubois and coworkers
point out that after challenge with antigen, T cell-dependent B cell activation and maturation occurs within extrafollicular regions of peripheral lymphoid tissues (32).
So one likely sequence is that DCs process antigen, migrate
to the T cell zones in peripheral lymphoid tissues and there
both activate naive T cells and are activated by T cells (1, 4,
17). Antigen-specific B cells in these T cell regions then
could form clusters with T cells and their associated DCs (13, 14) and receive signals from both cell types. Since both T cells and B cells enter the spleen through marginal zones
(35) and most CD40L+ T cells are found within periarteriolar lymphoid sheaths (PALS) (36), it would be interesting
to know whether or not during an immune response B cells
actually associate with DCs in these regions, e.g., along the
outer edge of the PALS as they migrate into primary follicles.
Another potential site where DCs might encounter and
regulate B cells is the germinal center (GC). It had been
thought that DCs in lymphoid tissues, such as interdigitating DCs, are relatively restricted to T cell zones. However,
GCs also contain specialized CD4+ CD11c+ DCs, designated GCDCs (37), which as potent activators of T cells may
function to sustain GC memory T cells or promote T-B interactions within germinal centers. Although Grouard et al. (37) suggest that GCDCs most likely function by stimulating GC T cells, they also show that GCDCs express both
complement and Fc receptors opening the possibility that
immune complexes on GCDCs may regulate GC memory B cells. While germinal centers persist for only ~3 wk
after immunization, memory B blasts continue to proliferate in follicles for months after the onset of T cell-dependent antibody responses (32). These cells are probably the source of plasma cells and memory cells required to maintain longterm antibody production and could well be regulated by
GCDCs. Follicular B cells can be induced to differentiate
into plasmablasts by signals such as IL-1 (32, 38), which
DCs can produce. Furthermore, some plasmablasts and plasma
cells express CD28 (39); thus, GCDCs (37) and other DCs
that can express CD80/86 might be able to sustain or
stimulate CD28+ plasmablasts through the CD28 pathway.
Clearly, much remains to be done beyond these suggestive
studies (16, 21, 37) to define the molecular mechanisms involved in DC-B cell interactions and their roles in human
diseases involving dysregulated B cells such as lymphomas
and autoimmune diseases.
(e.g., 2, 24-27), all of which can promote B cell maturation
(28). The types of chemokines DC lineage cells can make
such as macrophage inflammatory protein-1 gamma (29) are just beginning to be defined. It will be important to
compare CD1a+ versus CD1a
DCs for their ability to
make known B cell-stimulating factors such as IL-11 and
chemokines as well as to assess whether B cells produce factors that can regulate or attract DCs (30, 31).
Address correspondence to Edward A. Clark, Dept. Microbiology, Box 357242, University of Washington Medical Center, Seattle, WA 98195.
Received for publication 16 January 1997.
I thank Carl June for a nice discussion.This work was supported by National Institutes of Health grants GM37905 and RR00166.
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