title: FcRγ controls the fas-dependent regulatory function of lymphoproliferative double negative T cells.
abstract: Patients with autoimmune lymphoproliferative syndrome (ALPS) and lymphoproliferation (LPR) mice are deficient in Fas, and accumulate large numbers of αβ-TCR(+), CD4(-), CD8(-) double negative (DN) T cells. The function of these DN T cells remains largely unknown. The common γ subunit of the activating Fc receptors, FcRγ, plays an important role in mediating innate immune responses. We have shown previously that a significant proportion of DN T cells express FcRγ, and that this molecule is required for TCR transgenic DN T cells to suppress allogeneic immune responses. Whether FcRγ plays a critical role in LPR DN T cell-mediated suppression of immune responses to auto and allo-antigens is not known. Here, we demonstrated that FcRγ(+), but not FcRγ(-) LPR DN T cells could suppress Fas(+) CD4(+) and CD8(+) T cell proliferation in vitro and attenuated CD4(+) T cell-mediated graft-versus host disease. Although FcRγ expression did not allow LPR DN T cells to inhibit the expansion of Fas-deficient cells within the LPR context, adoptive transfer of FcRγ(+), but not FcRγ(-), DN T cells inhibited lymphoproliferation in generalized lymphoproliferative disease (GLD) mice. Furthermore, FcRγ acted in a cell-intrinsic fashion to limit DN T cell accumulation by increasing the rate of apoptosis in proliferated cells. These results indicate that FcRγ can confer Fas-dependent regulatory properties on LPR DN T cells, and suggest that FcRγ may be a novel marker for functional DN Tregs.
authors.affiliation: Institute of Medical Science, University of Toronto, Toronto, Ontario, Canada.
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Juvet
authors.forename: Christopher W
authors.initials: CW
authors.lastname: Thomson
authors.forename: Edward Y
authors.initials: EY
authors.lastname: Kim
authors.forename: Mei
authors.initials: M
authors.lastname: Han
authors.forename: Li
authors.initials: L
authors.lastname: Zhang
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D056735:Autoimmune Lymphoproliferative Syndrome / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D015704:CD4 Antigens / Q000235:genetics / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology / Q000637:transplantation; D016827:CD8 Antigens / Q000235:genetics / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology / Q000637:transplantation; D049109:Cell Proliferation; D005260:Female; D017353:Gene Deletion; D005786:Gene Expression Regulation; D006801:Humans; D007113:Immunity, Innate; D008297:Male; D051379:Mice; D017452:Receptors, IgG / Q000235:genetics / Q000276:immunology*; D019014:fas Receptor / Q000172:deficiency / Q000235:genetics / Q000276:immunology*
chemical_list: D015704:CD4 Antigens; D016827:CD8 Antigens; C491901:FAS protein, human; D017452:Receptors, IgG; D019014:fas Receptor