Search

T cell differentiation in the thymus is driven by positive selection through the interaction of αβ T cell receptors (TCRs) with self-peptides bound to self-major histocompatibility complex molecules, yet the influence of the peptide sequence on this process remains unknown. To address this issue, we have compared CD4+T cell differentiation between two sets of mouse lines in which MHC class II I-Abmolecules are occupied with either Eα chain-derived peptide (pEα) or its variant,p60K, with one amino acid substitution from leucine to lysine at P5 residue of TCR contacts. Here, we show that despite the comparable expression of I-Ab–peptide complex in the thymus, this substitution from leucine to lysine affects efficiency of positive selection, resulting in extremely small numbers of CD4+T cells to be selected to mature on I-Ab–p60K complex. Furthermore, we show that, although I-Ab–pEα complex selects diverse T cells, T cell repertoire shaped by I-Ab–p60K complex is markedly constrained. Our findings thus suggest that positive selection is both specific and degenerate, depending on the amino acid residues at TCR contacts of the selecting self-peptides.

Using gel retardation and in vitro "footprinting", we have analyzed the interactions between nuclear proteins derived from various mouse cells and the enhancer and interferon response sequences of the H-2Kb gene. We have found that a protein factor binds a site in the enhancer sequence that partially overlaps the interferon response sequence. This factor also binds to a similar sequence lying in the opposite orientation in the promoter of the mouse beta 2-microglobulin gene, suggesting a common regulatory mechanism. Transfection competition experiments indicate that this factor acts as a positive element in the expression of H-2 and beta 2-microglobulin genes.