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Editing Autoreactive TCR Enables Efficient Positive Selection¹

Fabio R. Santori, Ivica Arsov², Mirjana Lili and Stanislav Vukmanovi³

Michael Heidelberger Division of Immunology, Department of Pathology and Kaplan Cancer Center, New York University School of Medicine, New York, NY 10016

Allelic exclusion is inefficient at the TCR locus, allowing a sizeable portion of T cells to carry two functional TCRs. The potential danger of dual TCR expression is a rescue of autoreactive TCRs during selection in the thymus and subsequent development of autoimmunity. In this study, we examine the reason(s) for replacing an autoreactive TCR and for allowing the survival of cells carrying two TCRs. We compared development of TCR transgenic CD4⁺CD8^- thymocytes in the presence or absence of MHC class II autoantigen that does not induce deletion of thymocytes. Contrary to the expected negative effect of the presence of autoantigen, 100% more CD4⁺CD8^- thymocytes were found in the presence of MHC class II autoantigen than in the neutral background. A further increase in the strength of autoantigenic signal via expression of a human CD4 transgene led to an additional increase in the numbers of CD4⁺CD8^- thymocytes. Thus, editing autoreactive TCR results in more efficient positive selection, and this may be both a reason and a reward for risking autoimmunity.