The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1998/7/415/ $5.00
The Journal of Experimental Medicine, Volume 188, Number 2, July 20, 1998 415-420

Brief Definitive Reports

The Peripheral Deletion of Autoreactive CD8+ T Cells Induced by Cross-presentation of Self-antigens Involves Signaling through CD95 (Fas, Apo-1)

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

From the * Immunology Division of The Walter and Eliza Hall Institute of Medical Research, Parkville 3050, Victoria, Australia; and {ddagger} 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

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: heath{at}wehi.edu.au 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: carbone{at}cobra.path.monash.edu.au

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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