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.
Highlights
Naıve CD4+ T cells acquire various phenotypes during peripheral activation and expansion
To first exclude that the adjuvant determined the induction of cytolytic properties, we immunized BALB/c mice with the peptide adsorbed on alum, which elicited CD4+ T cells with comparable cytolytic activity
In a number of additional experiments we showed that the anti-FasL antibody restored up to 80% of WEHI-231 cell survival, whereas no significant restoration of survival was obtained with granzyme B (GZB) inhibitor z-AADfmk (Figure S6B, right panel), indicating that GZB did not account for much of the cytolysis of B cells
Summary
Naıve CD4+ T cells acquire various phenotypes during peripheral activation and expansion. We have investigated the possibility of varying amino acid residues located in epitope flanking regions to modulate the strength of the synapse formed by cognate recognition of a peptide-MHC complex, thereby altering CD4+ T cell properties These studies were encouraged by our previously reported observations [8], in which a CD4+ T cell clone acquired cytolytic properties with induction of apoptosis of antigen-presenting cells by exposure to an epitope containing a cysteine in its flanking residues. The studies reported here provide the demonstration that activation of CD4+ T cells by natural peptides encompassing class II-restricted epitopes and a thiol-disulfide oxidoreductase motif within flanking residues is sufficient to increase the strength of CD4 T cell stimulation This results in acquisition of cytolytic properties and elimination of APCs by apoptosis induction
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