Increased synapse formation obtained by T cell epitopes containing a CxxC motif in flanking residues convert CD4+ T cells into cytolytic effectors

PLoS One. 2012;7(10):e45366. doi: 10.1371/journal.pone.0045366. Epub 2012 Oct 9.

Abstract

The nature of MHC class II-binding epitopes not only determines the specificity of T cell responses, but may also alter effector cell functions. Cytolytic CD4+ T cells have been observed primarily in anti-viral responses, but very little is known about the conditions under which they can be elicited. Their potential as regulators of immune responses, however, deserves investigations. We describe here that inclusion of a thiol-disulfide oxidoreductase motif within flanking residues of class II-restricted epitopes results, both in vitro and in vivo, in elicitation of antigen-specific cytolytic CD4+ T cells through increased synapse formation. We show that both naïve and polarized CD4+ T cells, including Th17 cells, can be converted by cognate recognition of such modified epitopes. Cytolytic CD4+ T cells induce apoptosis on APCs by Fas-FasL interaction. These findings potentially open the way towards a novel form of antigen-specific immunosuppression.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Motifs / genetics
  • Amino Acid Motifs / immunology
  • Amino Acid Sequence
  • Animals
  • Antigen-Presenting Cells / immunology
  • Antigen-Presenting Cells / metabolism
  • Apoptosis / genetics
  • Apoptosis / immunology
  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / metabolism
  • Cell Proliferation
  • Cells, Cultured
  • Epitopes, T-Lymphocyte / genetics
  • Epitopes, T-Lymphocyte / immunology*
  • Epitopes, T-Lymphocyte / metabolism
  • Fas Ligand Protein / genetics
  • Fas Ligand Protein / immunology
  • Fas Ligand Protein / metabolism
  • Flow Cytometry
  • Histocompatibility Antigens Class II / genetics
  • Histocompatibility Antigens Class II / immunology
  • Histocompatibility Antigens Class II / metabolism
  • Immunological Synapses / immunology*
  • Mice
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Molecular Sequence Data
  • Mutation
  • Myelin-Oligodendrocyte Glycoprotein / immunology
  • Peptide Fragments / immunology
  • Protein Disulfide Reductase (Glutathione) / genetics
  • Protein Disulfide Reductase (Glutathione) / immunology
  • Protein Disulfide Reductase (Glutathione) / metabolism
  • Reverse Transcriptase Polymerase Chain Reaction
  • Sequence Homology, Amino Acid
  • T-Lymphocytes, Cytotoxic / immunology*
  • T-Lymphocytes, Cytotoxic / metabolism
  • fas Receptor / genetics
  • fas Receptor / immunology
  • fas Receptor / metabolism

Substances

  • Epitopes, T-Lymphocyte
  • Fas Ligand Protein
  • Histocompatibility Antigens Class II
  • Myelin-Oligodendrocyte Glycoprotein
  • Peptide Fragments
  • fas Receptor
  • myelin oligodendrocyte glycoprotein (35-55)
  • Protein Disulfide Reductase (Glutathione)

Grant support

The work was supported by University of Leuven/Collen Research foundation funding. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.