Divergent changes in the sensitivity of maturing T cells to structurally related ligands underlies formation of a useful T cell repertoire

CD4(+)CD8(+) thymocyte differentiation requires TCR signaling induced by se lf-peptide/MHC ligands. Nevertheless, the resulting mature T cells are not activated by these self-complexes, whereas foreign ligands can be potent st imuli. Here, we show that the signaling properties of TCR change during thy mocyte maturation, differentially affecting responses to related peptide/MH C molecule complexes and contributing to this discrimination. Weak agonists for CD4(+)CD8(+) thymocytes lose potency during development, accompanied b y a change in TCR-associated phosphorylation from an agonist to a partial a gonist/antagonist pattern. in contrast, sensitivity to strong agonists is m aintained, along with full signaling. This yields a mature T cell pool high ly responsive to foreign antigen while possessing a wide margin of safety a gainst activation by self-ligands.