Autospecific γδ thymocytes that escape negative selection find sanctuary in the intestine

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Abstract

αβ or γδ thymocytes whose T-cell receptors (TCRs) recognize endogenously expressed antigens (Ag) are autospecific and, thus, potentially self-reactive. In the thymus, such T cells are eliminated during T-cell development through a process known as negative selection. As a model of negative selection of γδ T cells, we have used G8 γδ–T cell transgenic mice, which express a γδ TCR that recognizes the nonpolymorphic MHC class I TLb molecule. Here, we demonstrate that negative selection of autospecific γδ T cells is almost complete in the adult thymus but is markedly attenuated in the neonatal thymus. A consequence of this attenuated negative selection is that potentially self-reactive γδ thymocytes are allowed to escape negative selection, undergo extrathymic differentiation, and find sanctuary in the intestinal epithelium. Interestingly, the ability of these potentially self-reactive γδ T cells to find sanctuary requires both the intestinal epithelial environment and the extrathymic presence of the self-Ag. The implications of these findings on the development and persistence of autoreactive T cells in autoimmune disease are discussed.

Authors

Tesu Lin, Hiroki Yoshida, Goro Matsuzaki, Sarah R. Guehler, Kikuo Nomoto, Terrence A. Barrett, Douglas R. Green