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J. Exp. Med.,
Volume 188, Number 2, July 20, 1998 415-420
By
From the * Immunology Division of The Walter and Eliza Hall Institute of Medical Research, Parkville
3050, Victoria, Australia; and 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 Department of Pathology and Immunology, Monash Medical
School, Prahran 3181, Victoria, Australia
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