An endogenous peptide positively selects and augments peripheral CD4(+) T cell activation and survival

Although CD4(+) and CD8(+) T cells differ in their positively selecting signal strength, endogenous positively selecting ligands have only been identified for MHC class I-restricted T cell receptors (TCRs). Here we screened for ligands that can positively select MHC class II-restricted TCRs, using thymocytes from four I-E(k) restricted TCR transgenic mice and a large panel of self peptides. One peptide, gp250, induced positive selection of AND CD4(+) T cells, had no homology with the AND TCR agonist ligand, and was recognized with a high degree of specificity. gp250 acted as a co-agonist to initiate activation and enhance survival of peripheral AND CD4(+) T cells. Thus, positively selecting ligands play critical roles in thymocyte development and in the activation and maintenance of peripheral T cells.