FcRc Controls the Fas-Dependent Regulatory Function of Lymphoproliferative Double Negative T Cells

Patients with autoimmune lymphoproliferative syndrome (ALPS) and lymphoproliferation (LPR) mice are deficient in Fas, and accumulate large numbers of ab-TCR+, CD42, CD82 double negative (DN) T cells. The function of these DN T cells remains largely unknown. The common c subunit of the activating Fc receptors, FcRc, plays an important role in mediating innate immune responses. We have shown previously that a significant proportion of DN T cells express FcRc, and that this molecule is required for TCR transgenic DN T cells to suppress allogeneic immune responses. Whether FcRc 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 FcRc+, but not FcRc2 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 FcRc expression did not allow LPR DN T cells to inhibit the expansion of Fas-deficient cells within the LPR context, adoptive transfer of FcRc+, but not FcRc2, DN T cells inhibited lymphoproliferation in generalized lymphoproliferative disease (GLD) mice. Furthermore, FcRc 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 FcRc can confer Fas-dependent regulatory properties on LPR DN T cells, and suggest that FcRc may be a novel marker fo