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Brief Definitive Reports

Christian Kurts^*,, William R. Heath^*, Hiroshi Kosaka^*, Jacques F.A.P. Miller^*, and Francis R. Carbone

From the ^* Immunology Division of The Walter and Eliza Hall Institute of Medical Research, Parkville 3050, Victoria, Australia; and The Department of Pathology and Immunology, Monash Medical School, Prahran 3181, Victoria, Australia

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.

Key Words: CD8⁺ T lymphocytes • T cell tolerance • apoptosis • CD95 • tumor necrosis factor receptor 2

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.

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