Long-term persistence of CD4(+) but rapid disappearance of CD8(+) T cells expressing an MHC class I-restricted TCR of nanomolar affinity

Mol Ther. 2012 Mar;20(3):652-60. doi: 10.1038/mt.2011.286. Epub 2012 Jan 10.


Most T cells have T cell receptors (TCR) of micromolar affinity for peptide-major histocompatibility complex (MHC) ligands, but genetic engineering can generate TCRs of nanomolar affinity. The affinity of the TCR used, m33, for its cognate non-self peptide-MHC-I complex (SIYRYYGL-K(b)) is 1,000-fold higher than of the wild-type TCR 2C. The affinity of m33 for the self-peptide dEV-8 on K(b) is only twofold higher. Mouse CD8(+) T cells transduced with an m33-encoding retrovirus showed binding of SIY-K(b) and potent function in vitro, but in vivo these T cells disappeared within hours after transfer into syngeneic hosts without causing graft-versus-host disease (GVHD). Accordingly, in cases where such CD8-dependent self-reactivity might occur in human adoptive T cell therapies, our results show that a peripheral T-cell deletion mechanism could operate to avoid reactions with the host. In contrast to CD8(+) T cells, we show that CD4(+) T cells expressing m33 survived for months in vivo. Furthermore, the m33-transduced CD4(+) T cells were able to mediate antigen-specific rejection of 6-day-old tumors. Together, we show that CD8(+) T cell expressing a MHC class I-restricted high-affinity TCR were rapidly deleted whereas CD4(+) T cells expressing the same TCR survived and provided function while being directed against a class I-restricted antigen.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / metabolism
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / metabolism
  • Cell Line
  • Cell Survival / immunology
  • Gene Expression
  • Genetic Vectors / genetics
  • Histocompatibility Antigens Class I / immunology*
  • Immunotherapy, Adoptive
  • Mice
  • Mice, Inbred C3H
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Neoplasms / genetics
  • Neoplasms / immunology
  • Neoplasms / therapy
  • Oligopeptides / immunology
  • Peptides / chemistry
  • Peptides / immunology
  • Receptors, Antigen, T-Cell / genetics*
  • Receptors, Antigen, T-Cell / immunology*
  • Retroviridae / genetics
  • Transduction, Genetic


  • Histocompatibility Antigens Class I
  • Oligopeptides
  • Peptides
  • Receptors, Antigen, T-Cell
  • superagonist SIYR