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Integrated Department of Immunology, University of Colorado School of Medicine and National Jewish Medical and Research Center, Denver, CO 80206; and
Departments of Medicine and Pathology, Center for Immunology, Howard Hughes Medical Institute, Washington University School of Medicine, St. Louis, MO 63110
Immature B cells display increased sensitivity to tolerance
induction compared with their mature counterparts. The molecular
mechanisms underlying these differences are poorly defined. In this
study, we demonstrate unique maturation stage-dependent differences in
B cell Ag receptor (BCR) signaling, including BCR-mediated calcium
mobilization responses. Immature B cells display greater increases in
intracellular calcium concentrations following Ag stimulation. This has
consequences for the induction of biologically relevant responses:
immature B cells require lower Ag concentrations for activation than
mature B cells, as measured by induction of receptor editing and CD86
expression, respectively. BCR-induced tyrosine phosphorylation of
CD79a, Lyn, B cell linker protein, and phospholipase C
2 is
enhanced in immature B cells and they exhibit greater capacitative
calcium entry in response to Ag. Moreover, B cell linker protein,
Bruton’s tyrosine kinase, and phospholipase C2, which are crucial
for the induction of calcium mobilization responses, are present at
3-fold higher levels in immature B cells, potentially contributing
to increased mobilization of calcium. Consistent with this possibility,
we found that the previously reported lack of
inositol-1,4,5-triphosphate production in immature B cells may be
explained by enhanced inositol-1,4,5-triphosphate breakdown. These data
demonstrate that multiple mechanisms guarantee increased Ag-induced
mobilization of calcium in immature B cells and presumably ensure
elimination of autoreactive B cells from the
repertoire.
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