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

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Abstract
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:MHCAcomplexes 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:MHCAwere present at the same frequency in hosts that expressed MHCAor a different MHC isoform (MHCB). However, most of the clones in MHCBhosts also recognized self peptide:MHCAcomplexes. When these “alloreactive” T cells were removed from the MHCBrepertoire via negative selection in an MHCAhost, 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 MHCAwas not required to produce foreign peptide:MHCA-binding clones, it had a large effect on selecting responsive clones.