A polyclonal model for B-cell tolerance. II. Linkage between signaling of B-cell egress from G0, class II upregulation and unresponsiveness.
Overnight exposure of adult splenic B cells to anti-Ig, a surrogate for antigen/tolerogen, can result in a hyporesponsive state in terms of antibody synthesis. Since B cells treated with either intact of F(ab')2 fragments of anti-Ig will exit the G0 phase of the cell cycle and enter G1 or S, respectively, we examined which steps in B-cell activation were required for this form of hyporesponsiveness. We found that B-cell hyporesponsiveness could be induced under conditions leading to either abortive or productive B-cell cycle progression, depending on the immunogenic challenge employed. Thus, PMA + ionomycin, concanavalin A, PMA alone, or ionomycin alone induced hyporesponsiveness. Each of these reagents is able to drive B-cell exit from G0 into G1 and cause class II hyperexpression. We next examined the effect of cyclosporin A (CSA), a reagent that blocks anti-Ig but not by PMA-induced class II hyperexpression. Interestingly, CSA only interfered with the induction of B-cell hyporesponsiveness with anti-Ig. These results suggest that upregulation of MHC class II may be coincident with a CSA-sensitive tolerance pathway in B cells stimulated by anti-Ig. Finally, IL-4 pretreatment was found to ablate hyporesponsiveness induced by either intact anti-Ig or PMA. These results parallel the Fc-dependent induction of hyporesponsiveness reported earlier (G. Warner and D. W. Scott, J. Immunol. 146, 2185, 1991). We propose that crosslinking of surface Ig, leading to cell cycle progression out of G0 as well as class II hyperexpression, in the absence of a cognate T cell signal, leads to B-cell hyporesponsiveness.
Warner
G L
GL
Immunology Division, University of Rochester Cancer Center, New York 14642.
Gaur
A
A
Scott
D W
DW
D000818:Animals; D000943:Antigens, Differentiation / Q000502:physiology; D001402:B-Lymphocytes / Q000276:immunology*; D003208:Concanavalin A; D016572:Cyclosporine / Q000494:pharmacology; D000949:Histocompatibility Antigens Class II / Q000032:analysis*; D007108:Immune Tolerance; D015847:Interleukin-4 / Q000494:pharmacology; D008213:Lymphocyte Activation; D051379:Mice; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D008954:Models, Biological; D011493:Protein Kinase C / Q000502:physiology; D011947:Receptors, Antigen, B-Cell / Q000502:physiology; D011961:Receptors, Fc / Q000502:physiology; D017452:Receptors, IgG; D016192:Resting Phase, Cell Cycle; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D015854:Up-Regulation
D000943:Antigens, Differentiation; D000949:Histocompatibility Antigens Class II; D011947:Receptors, Antigen, B-Cell; D011961:Receptors, Fc; D017452:Receptors, IgG; D003208:Concanavalin A; D015847:Interleukin-4; D016572:Cyclosporine; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate