Deciphering CD4+ T cell specificity using novel MHC-TCR chimeric receptors

Nat Immunol. 2019 May;20(5):652-662. doi: 10.1038/s41590-019-0335-z. Epub 2019 Mar 11.


αβ T cell antigen receptors (TCRs) bind complexes of peptide and major histocompatibility complex (pMHC) with low affinity, which poses a considerable challenge for the direct identification of αβ T cell cognate peptides. Here we describe a platform for the discovery of MHC class II epitopes based on the screening of engineered reporter cells expressing novel pMHC-TCR (MCR) hybrid molecules carrying cDNA-derived peptides. This technology identifies natural epitopes of CD4+ T cells in an unbiased and efficient manner and allows detailed analysis of TCR cross-reactivity that provides recognition patterns beyond discrete peptides. We determine the cognate peptides of virus- and tumor-specific T cells in mouse disease models and present a proof of concept for human T cells. Furthermore, we use MCR to identify immunogenic tumor neo-antigens and show that vaccination with a peptide naturally recognized by tumor-infiltrating lymphocytes efficiently protects mice from tumor challenge. Thus, the MCR technology holds promise for basic research and clinical applications, allowing the personalized identification of T cell-specific neo-antigens in patients.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Base Sequence
  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / metabolism
  • Cell Line, Tumor
  • Cells, Cultured
  • Epitopes, T-Lymphocyte / genetics
  • Epitopes, T-Lymphocyte / immunology
  • Epitopes, T-Lymphocyte / metabolism
  • Humans
  • Major Histocompatibility Complex / genetics
  • Major Histocompatibility Complex / immunology*
  • Mice, Inbred C57BL
  • Peptides / genetics
  • Peptides / immunology
  • Peptides / metabolism
  • Receptors, Antigen, T-Cell / genetics
  • Receptors, Antigen, T-Cell / immunology*
  • Receptors, Antigen, T-Cell / metabolism
  • Receptors, Chimeric Antigen / genetics
  • Receptors, Chimeric Antigen / immunology*
  • Receptors, Chimeric Antigen / metabolism
  • T-Cell Antigen Receptor Specificity / immunology*


  • Epitopes, T-Lymphocyte
  • Peptides
  • Receptors, Antigen, T-Cell
  • Receptors, Chimeric Antigen