How cytotoxic T cells manage to discriminate nonself from self at the nonapeptide level.

Class I major histocompatibility complex (MHC) antigens are confronted with an apparently insurmountable dilemma. Each should show a binding preference to a common enough variety of nonapeptides, so that one relevant nonapeptide can be found in at least every other viral protein to provoke a cytotoxic T-cell response. By so doing, however, the chance of that viral T epitope being self is greatly increased. Examination of human and viral nonapeptides preferred by HLA-B27 led to the following conclusions. (i) In normal cells, peptide fragments originating from 5000 or more diverse proteins vie for a finite number of class I MHC sites. Consequently, only those nonapeptides having the optimal binding affinity to a given class I MHC antigen can gain access to the plasma membrane. (ii) Tolerance is rendered only to those host nonapeptides with the optimal binding affinity. (iii) Because of the above noted tolerance, viral nonapeptides with the optimal binding affinity are invariably ignored. (iv) Viral T epitopes actually chosen are always second-echelon nonapeptides that are endowed with slightly less than the optimal binding affinity to a given class I MHC antigen. (v) Since such second-echelon nonapeptides would not gain access to the plasma membrane in normal cells, the issue of self or nonself is rendered irrelevant by this choice. (vi) Since viral T epitopes are of this type, cytotoxic T-cell responses against infected cells are expected to be effective only when a few viral proteins are made in large amounts at the expense of host proteins.