THE PERIPHERAL DELETION OF AUTOREACTIVE CD8(-CELLS INDUCED BY CROSS-PRESENTATION OF SELF-ANTIGENS INVOLVES SIGNALING THROUGH CD95 (FAS, APO-1)() T)

Recently, we demonstrated that major histocompatibility complex class I-restricted cross-presentation of exogenous self-antigens can induce peripheral T cell tolerance by deletion of autoreactive CD8(+) T cells . In these studies, naive ovalbumin (OVA)-specific CD8(+) T cells from the transgenic line OT-I were injected into transgenic mice expressin g membrane-bound OVA (mOVA) under the control of the rat insulin promo ter (RIP) in pancreatic islets, kidney proximal tubules, and the thymu s. Cross-presentation of tissue-derived OVA in the renal and pancreati c lymph nodes resulted in activation, proliferation, and then the dele tion of OT-I cells. In this report, we investigated the molecular mech anisms underlying this form of T cell deletion. OT-I mice were crossed to tumor necrosis factor receptor 2 (TNFR2) knockout mice and to CD95 (Fas, Apo-1) deficient mutant lpr mice. Wild-type and TNFR2-deficient OT-I cells were activated and then deleted when transferred into RIP- mOVA mice, whereas CD95-deficient OT-I cells were not susceptible to d eletion by cross-presentation. Furthermore, cross-presentation led to upregulation of the CD95 molecule on the surface of wild-type OT-I cel ls in vivo, consistent with the idea that this is linked to rendering autoreactive T cells susceptible to CD95-mediated signaling. This stud y represents the first evidence that CD95 is involved in the deletion of autoreactive CD8(+) T cells in the whole animal.