Developmentally regulated association of a 56-kD member of the surface immunoglobulin M receptor complex.

Abstract

SummaryImmature and mature B cells differ in the signals generated and transduced through their antigen receptor, surface immunoglobulin M (slgM). Whereas signals generated through slgM on mature B cells initiate a program leading to the positive activation of these cells, signaling through this receptor at the immature stage of development leads to a state of induced unresponsiveness or tolerance. Our previous studies have described developmental differences in slgM transmembrane signaling that are independent of ligand-receptor affinity. In an attempt to understand the molecular basis for signaling differences between immature and mature B cells, we have analyzed the slgM receptor complex in neonatal and adult mouse splenic B cells. While previously described components of this complex do not exhibit marked developmentally regulated differences in their association with slgM, we have identified a 56-kD protein that associates with slgM in mature (antigenresponsive), but not immature (tolerance-sensitive) B cells. This protein (p56) associates with slgM as a homodimer, is constitutively phosphorylated on tyrosine, and is coimmunoprecipitated with IgM but not IgD. The observed inability to iodinate p56 suggests it is an intracellular component of the receptor complex. Based upon its migration in one-and two-dimensional gel electrophoresis we show, however, that p56 is distinct from the blk, lyn, or fyn src family kinases that have been shown to be associated with slgM in mature B cells. The developmentally regulated participation of p56 in the B cell antigen receptor complex suggests a role in the differential signaling mediated via slgM on immature and mature B cells. (7), while all populations of immature B cells manifest the transmembrane signaling defect. Indeed, this membrane-associated signaling difference appears to be the primary mechanism accounting for the unresponsiveness of neonatal splenic B cells to anti-/~ antibody stimulation (5).

The bcl-2 gene product inhibits clonal deletion of self-reactive B lymphocytes in the periphery but not in the bone marrow.

“…Although both immature and mature self-reactive B cells have been shown to be clonally deleted by signaling via slg receptors upon interaction with self-antigens (10,11), mechanisms for antigen-induced elimination of self-reactive B cells appear to be different in immature and mature B cells. This could be due to the fact that signaling pathways via slg receptors are different between the two stages of B cells (11,12). Different responses to self-antigen stimulation by immature and mature B cells were also shown by recent studies on autoantibody transgenic mice (27,28) demonstrating that cross-linking of slg induced replacement of the Ig r chain in self-reactive immature B cells, not in mature B cells.…”

“…Immature B cells do not respond to cross-linking of the slg in vitro, whereas the same stimulation induces DNA synthesis in mature B cells (11). Further evidence comes from the observation that slg-associated molecules and signal transduction pathways via slg receptor complexes are different in immature and mature B cells (12). In spite of these differences, no data refer to distinct tolerance mechanisms between B cells in the bone marrow and the periphery.…”