title: FcRγ promotes T cell apoptosis in Fas-deficient mice.
abstract: Deficiency of Fas or its ligand leads to lymphocyte accumulation, lymphadenopathy, splenomegaly, and autoimmunity in mice and humans. Although the Fas pathway is important for limiting the number of peripheral T cells, inactivation of other pro-apoptotic molecules can also perturb T cell homeostasis independently of and/or in concert with Fas deficiency. Here, we show that combined deficiency of Fas and the Fc receptor common γ signaling chain (FcRγ) results in worsened T cell accumulation in comparison with mice lacking Fas alone, with a particularly marked increase in the number of TCRαβ(+)CD4(-)CD8(-) double negative (DN) T cells. LPR FcRγ(-/-) mice exhibited reduced survival due to progressive lymphadenopathy. We further investigated the mechanisms whereby FcRγ deficiency promotes lymphoproliferative disease in Fas-mutant mice. Interestingly, there were no significant differences in T cell proliferation between LPR FcRγ(+/+) and LPR FcRγ(-/-) mice in vivo and in vitro. However, FcRγ deletion resulted in significantly decreased peripheral T cell apoptosis. Importantly, the observed increase in apoptosis was restricted to a subset of FcRγ(+) T cells. These T cells, but not those lacking FcRγ expression, exhibited increased activation of caspases 3 and 9, indicating a role for FcRγ in driving their apoptosis. FcRγ(+) DN T cells also showed enhanced sensitivity to TCR restimulation-induced cell death (RICD) despite lacking Fas, suggesting that TCR stimulation of autoreactive T cells in vivo may serve to eliminate FcRγ(+) T cells and thus exert partial control over lymphoproliferative disease. Hence, our data reveal a novel role for FcRγ in promoting peripheral T cell apoptosis in Fas-deficient mice, which may be of significant value in understanding autoimmune lymphoproliferative syndromes.
authors: Division of Respirology, University Health Network, Toronto General Research Institute, University of Toronto, Toronto, ON, Canada M5G 1L7. Stephen.juvet@mail.utoronto.ca
authors: Stephen C
authors: SC
authors: Juvet
authors: Christopher W
authors: CW
authors: Thomson
authors: Edward Y
authors: EY
authors: Kim
authors: Betty
authors: B
authors: Joe
authors: Oyedele
authors: O
authors: Adeyi
authors: Li
authors: L
authors: Zhang
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D056735:Autoimmune Lymphoproliferative Syndrome / Q000276:immunology*; D015704:CD4 Antigens / Q000378:metabolism; D016827:CD8 Antigens / Q000378:metabolism; D053148:Caspase 3 / Q000378:metabolism; D053453:Caspase 9 / Q000378:metabolism; D048708:Cell Growth Processes / Q000235:genetics; D006801:Humans; D008206:Lymphatic Diseases / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D019463:Mice, Inbred MRL lpr; D018345:Mice, Knockout; D009154:Mutation / Q000235:genetics; D017452:Receptors, IgG / Q000235:genetics / Q000378:metabolism*; D013601:T-Lymphocytes / Q000276:immunology*; D019014:fas Receptor / Q000235:genetics / Q000378:metabolism*
chemical_list: D015704:CD4 Antigens; D016827:CD8 Antigens; D017452:Receptors, IgG; D019014:fas Receptor; D053148:Caspase 3; D053453:Caspase 9