Positive selection optimizes the number and function of MHCII-restricted CD4⁺ T cell clones in the naive polyclonal repertoire

T cell receptors (TCRs) on T lymphocytes in an individual bind foreign peptides bound to major histocompatibility complex (MHC) molecules expressed in that individual (designated MHCA). Results from radiation bone marrow chimeras and TCR transgenic mice indicate that this complex form of antigen recognition is the result of positive selection of clones with low affinity for self peptide:MHCA complexes during development. Here we used a sensitive peptide:MHC tetramer enrichment method to quantify the role of positive selection in the generation of the preimmune polyclonal T cell repertoire in normal individuals. We made the surprising observation that mouse and human naive T cells capable of binding to foreign peptide:MHCA were present at the same frequency in hosts that expressed MHCA or a different MHC isoform (MHCB). However, most of the clones in MHCB hosts also recognized self peptide:MHCA complexes. When these ''alloreactive'' T cells were removed from the MHCB repertoire via negative selection in anMHCA host, the number of foreign peptide:MHCA-binding T cells was reduced to one fifth and many of the remaining cells did not respond to the peptide. Therefore, although positive selection on MHCA was not required to produce foreign peptide:MHCA-binding clones, it had a large effect on selecting responsive clones.