Yin, Li; (1993) T cell recognition of endogenous and exogenous peptides presented by MHC molecules. Doctoral thesis (Ph.D), UCL (University College London).

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Abstract

This thesis presents data of analysing T cell responses to synthetic Ras peptides and to natural peptide epitopes derived from minor histocompatibility (mH) antigens. Murine T helper and cytotoxic T lymphocyte (CTL) responses were induced by synthetic peptides corresponding to amino acids 1-23 of the normal or mutant p21Ras proteins containing a glycine to valine mutation at position 12. Specific T helper responses against mutant Ras peptide were observed in C3H/He, B10.BR but not C57BL/10 mice. These responses were mediated by CD4+ cells and restricted by MHC class II molecules. Moreover, mutant Ras peptide-specific T helper cells recognised the corresponding intact p21Ras protein. Ras peptides also induced CTL which were classical CD8+aTCR+ T cells. None of the CTL could distinguish mutant and normal Ras peptides. Interestingly, these CTL lysed peptide pulsed murine cells of several different H-2 haplotypes, indicating that recognition was not MHC class I allele restricted. However, the real peptide epitopes recognised by these unconventional CTL were not identified since Ras peptides were not very pure and stable, and undefined minor components might be responsible for the CTL responses. mH antigens cause rejection of MHC matched transplants. Bulk CTL responses were generated in H-2b mice differing in one (H-1), two (H-1 and H-25) or multiple (>29) mH loci, and HPLC purification was used to analyse the complexity of CTL recognised peptides. Both anti-H-1 and anti- H-l/H-25 CTL recognised one immunodominant epitope which was encoded by the H-1 locus and presented by H-2Kb molecules. Anti-multiple mH antigen CTL recognised the same H-1 locus derived epitope and another genetically undefined epitope which was presented by H-2Db molecules. Subfractionation of the CTL recognised HPLC fractions suggested that one mH locus encodes probably no more than one CTL epitope. Attempts were made to microsequence the CTL epitopes.

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