T cell receptor recognition of MHC class II-bound peptide flanking residues enhances immunogenicity and results in altered TCR V region usage

Immunity. 1997 Sep;7(3):387-99. doi: 10.1016/s1074-7613(00)80360-x.


Naturally processed MHC class II-bound peptides possess ragged NH2 and COOH termini. It is not known whether these peptide flanking residues (PFRs), which lie outside the MHC anchor residues, are recognized by the TCR or influence immunogenicity. Here we analyzed T cell responses to the COOH-terminal PFR of the H-2A(k) immunodominant epitope of hen egg lysozyme (HEL) 52-61. Surprisingly, the majority of T cells were completely dependent on, and specific for, the COOH-terminal PFR of the immunogen. In addition, there were striking correlations between TCR V beta usage and PFR dependence. We hypothesize that the V alpha CDR1 region recognizes NH2-terminal PFRs, while the V beta CDR1 region recognizes COOH-terminal PFRs. Last, peptides containing PFRs were considerably more immunogenic and mediated a greater recall response to the HEL protein. These results demonstrate that PFRs, which are a unique characteristic of peptides bound to MHC class II molecules, can have a profound effect on TCR recognition and T cell function. These data may have important implications for peptide-based immunotherapy and vaccine development.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • Binding Sites
  • Epitopes
  • H-2 Antigens / immunology
  • H-2 Antigens / metabolism
  • H-2 Antigens / pharmacology
  • Histocompatibility Antigens Class II / immunology*
  • Histocompatibility Antigens Class II / metabolism*
  • Immunodominant Epitopes / immunology
  • Immunodominant Epitopes / metabolism
  • Immunoglobulin Variable Region / immunology*
  • Lymphocyte Activation
  • Mice
  • Mice, Inbred Strains
  • Molecular Sequence Data
  • Muramidase / immunology
  • Muramidase / metabolism
  • Muramidase / pharmacology
  • Peptides / immunology*
  • Peptides / metabolism*
  • Receptors, Antigen, T-Cell / immunology*
  • Receptors, Antigen, T-Cell / metabolism*
  • T-Lymphocytes / drug effects
  • T-Lymphocytes / immunology
  • T-Lymphocytes / physiology*


  • Epitopes
  • H-2 Antigens
  • Histocompatibility Antigens Class II
  • Immunodominant Epitopes
  • Immunoglobulin Variable Region
  • Peptides
  • Receptors, Antigen, T-Cell
  • antigen H-2A(k)
  • Muramidase