Altered antigen receptor signaling and impaired Fas-mediated apoptosis of B cells in Lyn-deficient mice.
Mice deficient in the src related protein tyrosine kinase, Lyn, exhibit splenomegaly and accumulate lymphoblast-like and plasma cells in spleen as they age, resulting in elevated levels of serum IgM (10-20-fold of control) and glomerulonephritis due to the presence of immune complexes containing auto-reactive antibodies. It remains unclear, however, how antibody-producing cells are accumulated in the lymphoid tissues of Lyn-/- mice. To elucidate the role of Lyn in B cell function, we have studied the proliferative responses to various stimuli and Fas-mediated apoptosis in B cells from young Lyn-/- mice which do not yet show apparent abnormality such as splenomegaly. Compared with control B cells, Lyn-/- B cells were hyper responsive to anti-IgM-induced proliferation and defective in Fc gamma RIIB-mediated suppression of B cell antigen receptor (BCR) signaling, indicating that Lyn is involved in the negative regulation of BCR signaling. In addition, the BCR-mediated signal in Lyn-/- B cells, unlike that in control B cells, failed to act in synergy with either CD40- or IL-4 receptor-triggered signal in inducing a strong proliferative response, suggesting that the BCR signaling pathway in Lyn-/- B cells is altered from that in control B cells. Furthermore, Lyn-/- B cells were found to be impaired in the induction of Fas expression after CD40 ligation and exhibited a reduced susceptibility to Fas-mediated apoptosis. Moreover, BCR cross-linking in Lyn-/- B cells suppressed Fas expression induced by costimulation with CD40 ligand and IL-4. Collectively, these results suggest that the accumulation of lymphoblast-like and plasma cells in Lyn-/- mice may be caused in part, by the accelerated activation of B cells in the absence of Lyn, as well as the impaired Fas-mediated apoptosis after the activation.
Wang
J
J
Medical Institute of Bioregulation, Kyushu University, Fukuoka, Japan.
Koizumi
T
T
Watanabe
T
T
D000818:Animals; D017209:Apoptosis; D001402:B-Lymphocytes / Q000166:cytology*; D002455:Cell Division; D002478:Cells, Cultured; D006041:Goats; D051379:Mice; D011947:Receptors, Antigen, B-Cell / Q000378:metabolism; D019014:fas Receptor / Q000502:physiology*; D019061:src-Family Kinases / Q000172:deficiency*
D011947:Receptors, Antigen, B-Cell; D019014:fas Receptor; C060902:lyn protein-tyrosine kinase; D019061:src-Family Kinases