Weak agonist self‐peptides promote selection and tuning of virus‐specific T cells

Recent progress has begun to define the interactions and signaling pathways that are triggered during positive selection. To identify and further examine self‐peptides that can mediate positive selection, we searched a protein‐database to find peptides that have minimal homology with the viral peptide (p33) that activates a defined P14 transgenic TCR. We identified four peptides that could bind the restriction element H‐2Db and induce proliferation of P14 transgenic splenocytes at high concentration. Two of the four peptides (DBM and RPP) were able to positively select thevirus‐specific TCR in fetal thymic organ culture but were unable to induce clonal deletion. Reverse‐phase HPLC and mass spectrometry demonstrated that these peptides were presented by H‐2Db molecules on thymic epithelial cell lines. We also examined whether the selecting ligands altered T cell responsiveness in vitro. DBM‐selected T cells lost their ability to respond to the positively selecting ligand DBM, whereas RPP‐selected T cells only retainrd their ability to respond to high concentrations of RPP. These results demonstrate that self‐peptides that mediate positiveselection can differentially "tune" the activation threshold of T cells and alter the functional repertoire of T cells.