INTERACTIONS WITH MULTIPLE PEPTIDE LIGANDS DETERMINE THE FATE OF DEVELOPING THYMOCYTES

Thymocytes are positively or negatively selected depending on interact ions between their T cell receptors (TCR) and peptides presented by ma jor histocompatibility complex molecules. We have previously shown tha t apoptosis of thymocytes from an alpha beta TCR-transgenic mouse (F5) , induced by antigenic peptide, can be inhibited specifically by an an tagonist peptide variant in an in vitro culture model. We have now ext ended these experiments by demonstrating that the antagonist peptide c an inhibit natural negative selection of maturing thymocytes, induced by endogenously expressed antigen, in fetal thymic organ cultures (FTO C), This inhibition resulted in the rescue and maturation of thymocyte s that would otherwise have been deleted. Mature T cells generated in these cultures were able to respond to antigen by producing limited qu antities of interferon-gamma, but unlike T cells from control FTOC, th ey required exogenous interleukin-2 to generate cytolytic effector cel ls, Interestingly, the antagonist peptide also accelerated the develop ment of F5 thymocytes in the absence of the negatively selecting ligan d, These data suggest that the developmental fate of a thymocyte may b e determined by the recognition of multiple distinct peptide ligands d uring thymic selection. Alterations in the profiles of selecting pepti des presented in the thymus would thus have profound effects on the si ze and autoreactive potential of the T cell repertoire generated.