Signaling through surface IgM in tolerance-susceptible immature murine B lymphocytes. Developmentally regulated differences in transmembrane signaling in splenic B cells from adult and neonatal mice.
During the course of B lymphocyte development, newly emerging surface Ig+ B cells pass through a stage when Ag-Ag receptor interactions lead not to immune responsiveness but to a state of functional tolerance. We have explored the molecular basis of antigenic nonresponsiveness and tolerance susceptibility using tolerance-susceptible surface Ig+ splenic B lymphocytes from neonatal mice and anti-mu chain antibodies as a polyclonal ligand. In this population of cells, surface IgM is uncoupled from the inositol phospholipid (PI)-hydrolysis pathway at a point proximal to the receptor; anti-mu antibodies did not stimulate inositol phosphate generation despite the fact that PI-hydrolysis was observed after treatment with A1F4, implicating the existence of a functional G protein and phospholipase C. Further evidence for a difference early in the signal transduction pathway stems from the finding that anti-mu stimulation does not induce the expression of two immediate/early PKC-linked genes egr-1 and c-fos. This appears to be the primary signaling difference between the mature and immature B cells from the neonatal mouse splenic population, as these cells undergo a G0-G1 cell cycle phase transition when surface IgM is bypassed using phorbol diester and calcium ionophore. Interestingly, despite undetectable levels of PI-hydrolysis, we observed equivalent receptor-mediated changes in intracellular calcium when comparing the immature and mature populations. These results indicate incomplete coupling of surface IgM to the signal transduction machinery operative in mature, immunocompetent B cells and suggests a molecular mechanism accounting for the differential processing of surface IgM signals into activation vs tolerogenic responses observed in these two stages of B cell development.
Yellen
A J
AJ
Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia 19104.
Glenn
W
W
Sukhatme
V P
VP
Cao
X M
XM
Monroe
J G
JG
D000375:Aging / Q000276:immunology; D000818:Animals; D000831:Animals, Newborn; D001402:B-Lymphocytes / Q000276:immunology*; D002118:Calcium / Q000378:metabolism; D002453:Cell Cycle / Q000187:drug effects; D003432:Cross-Linking Reagents; D007108:Immune Tolerance / Q000276:immunology*; D007075:Immunoglobulin M / Q000502:physiology*; D015759:Ionomycin / Q000494:pharmacology; D008213:Lymphocyte Activation; D051379:Mice; D008807:Mice, Inbred BALB C; D010716:Phosphatidylinositols / Q000378:metabolism; D011947:Receptors, Antigen, B-Cell / Q000502:physiology*; D015398:Signal Transduction / Q000276:immunology*; D013154:Spleen / Q000166:cytology; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D003432:Cross-Linking Reagents; D007075:Immunoglobulin M; D010716:Phosphatidylinositols; D011947:Receptors, Antigen, B-Cell; D015759:Ionomycin; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium