MODULATION OF T-CELL DEVELOPMENT BY AN ENDOGENOUS ALTERED PEPTIDE LIGAND

T cells potentially encounter numerous endogenous peptides during sele ction in the thymus and in the periphery. We examined the impact of an endogenous peptide on in vivo T cell development, using a TCR transge nic mouse model based on a hemoglobin-specific T cell clone. In these mice, the transgenic beta chains paired with endogenous alpha chains. This led to a serendipitous primary reactivity to Ser69 peptide, an al tered peptide ligand of the Hb(d) (64-76) epitope of the parent done. Two Ser69-reactive T cell populations were identified. A smaller popul ation of the Ser69-reactive T cells responded both to Ser69 and Hb(d) (64-76). A majority reacted only to Ser69, and not to Hb(d)(64-76); in fact, Hb(d)(64-76) was a specific TCR antagonist for these Ser69-only -reactive T cells. Thus, in this unique experimental system, Ser69 bec ame an agonist, and Hb(d) (64-76) was an antagonist. Endogenous presen tation of the antagonist ligand in the thymus selectively eliminated t he high-avidity cells, while sparing low-avidity cells in the Ser69-re active T cell repertoire. These results highlight how specificity guid es developing T cells through a network of ligands and indicate that t he endogenous peptide pool has a profound effect on T cell development and repertoire.