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Virus-Induced Activation of Self-Specific TCR CD8 Intraepithelial Lymphocytes Does Not Abolish Their Self-Tolerance in the Intestine¹

Leslie Saurer^2,*, Inge Seibold^*, Silvia Rihs^*, Claudio Vallan^*, Tilman Dumrese and Christoph Mueller^3,*

^* Institute of Pathology, Division of Immunopathology, University of Bern, Bern, Switzerland; and Department of Pathology, Institute of Experimental Immunology, University of Zurich, Zurich, Switzerland

TCR CD8 intestinal intraepithelial lymphocytes (IEL) represent an enigmatic subset of T cells, particularly, in regard to their potential functions and the apparent persistence of cells expressing self-specific TCR. We have used mice that are transgenic for the TCR specific for the lymphocytic choriomeningitis virus (LCMV)-derived peptide gp33, and TCR-transgenic mice that coexpress the gp33 Ag ubiquitously, to analyze the functional properties of TCR CD8 IEL in the presence, or absence, of their specific MHC-restricted Ag, and to assess the impact of molecular mimicry during a potent LCMV infection on potentially self-reactive TCR CD8 IEL. In this study, we show that the presence of the specific self-Ag results in reduced expression of IL-2, IFN-, and IL-10 by resident TCR CD8 IEL while expression of mRNA for TGF is not affected. We further demonstrate that despite their secluded location in the epithelium, TCR CD8 IEL are activated after infection of the intestinal mucosa with LCMV. Importantly, LCMV-induced activation of self-specific TCR CD8 IEL does not reverse their tolerance as no cytotoxic activity or up-regulated expression of proinflammatory cytokines is detected and no overt signs of autoimmunity are seen. Taken together, these results are in support of an immunoregulatory role for self-specific TCR CD8 in the intestinal mucosa and clearly speak against an involvement of this cell subset in inflammatory reactions and tissue destruction.

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