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 expressing membrane-bound OVA (mOVA) under the control of the rat insulin promoter (RIP) in pancreatic islets, kidney proximal tubules, and the thymus. Cross-presentation of tissue-derived OVA in the renal and pancreatic lymph nodes resulted in activation, proliferation, and then the deletion of OT-I cells. In this report, we investigated the molecular mechanisms 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 deletion by cross-presentation. Furthermore, cross-presentation led to upregulation of the CD95 molecule on the surface of wild-type OT-I cells in vivo, consistent with the idea that this is linked to rendering autoreactive T cells susceptible to CD95-mediated signaling. This study represents the first evidence that CD95 is involved in the deletion of autoreactive CD8+ T cells in the whole animal.
The Peripheral Deletion of Autoreactive CD8+ T Cells Induced by Cross-presentation of Self-antigens Involves Signaling through CD95 (Fas, Apo-1)
Address correspondence to William R. Heath, Immunology Division, The Walter and Eliza Hall Institute, P.O. Royal Melbourne Hospital, Parkville 3050, Victoria, Australia. Phone: 61-3-9345-2555; Fax: 61-3-9347-0852; E-mail: [email protected] or to Francis R. Carbone, The Department of Pathology and Immunology, Monash Medical School, Commercial Road, Prahran 3181, Victoria, Australia. Phone: 61-3-9276-2744; Fax: 61-3-9529-6484; E-mail: [email protected]
C. Kurts is supported by a fellowship from the Deutsche Forschungsgemeinschaft (Grant Ku1063/1-2). This work was funded by National Institutes of Health grant AI-29385 and grants from the National Health and Medical Research Council of Australia and the Australian Research Council.
Christian Kurts, William R. Heath, Hiroshi Kosaka, Jacques F.A.P. Miller, Francis R. Carbone; The Peripheral Deletion of Autoreactive CD8+ T Cells Induced by Cross-presentation of Self-antigens Involves Signaling through CD95 (Fas, Apo-1) . J Exp Med 20 July 1998; 188 (2): 415–420. doi: https://doi.org/10.1084/jem.188.2.415
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