Autospecific gamma delta thymocytes that escape negative selection find sanctuary in the intestine

alpha beta or gamma delta thymocytes whose T-cell receptors (TCRs) recogniz e endogenously expressed antigens (Ag) are autospecific and, thus, potentia lly 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 n egative selection of gamma delta T cells, we have used G8 gamma delta-T cel l transgenic mice, which express a gamma delta TCR that recognizes the nonp olymorphic MHC class ITLb molecule. Here, we demonstrate that negative sele ction of autospecific gamma delta T cells is almost complete in the adult t hymus but is markedly attenuated in the neonatal thymus. A consequence of t his attenuated negative selection is that potentially self-reactive gamma d elta thymocytes are allowed to escape negative selection, undergo extrathym ic differentiation, and find sanctuary in the intestinal epithelium. Intere stingly, the ability of these potentially self-reactive gamma delta 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 d isease are discussed.