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

Boris Engels, Adam S. Chervin, Andrea J. Sant, David M Kranz, Hans Schreiber

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)652-660
Number of pages9
JournalMolecular Therapy
Volume20
Issue number3
DOIs
StatePublished - Mar 2012

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T-Cell Antigen Receptor
Major Histocompatibility Complex
T-Lymphocytes
Peptides
Histocompatibility Antigens Class I
Genetic Engineering
Graft vs Host Disease
Retroviridae
Cell- and Tissue-Based Therapy
Ligands
Antigens

ASJC Scopus subject areas

  • Molecular Medicine
  • Molecular Biology
  • Genetics
  • Pharmacology
  • Drug Discovery

Cite this

Long-term persistence of CD4+ but rapid disappearance of CD8+ T cells expressing an MHC class I-restricted TCR of nanomolar affinity. / Engels, Boris; Chervin, Adam S.; Sant, Andrea J.; Kranz, David M; Schreiber, Hans.

In: Molecular Therapy, Vol. 20, No. 3, 03.2012, p. 652-660.

Research output: Contribution to journalArticle

Engels, Boris ; Chervin, Adam S. ; Sant, Andrea J. ; Kranz, David M ; Schreiber, Hans. / Long-term persistence of CD4+ but rapid disappearance of CD8+ T cells expressing an MHC class I-restricted TCR of nanomolar affinity. In: Molecular Therapy. 2012 ; Vol. 20, No. 3. pp. 652-660.
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