Activation of CD4+ CD25+ Regulatory T Cell Suppressor Function by Analogs of the Selecting Peptide

CD4+ CD25+ Foxp3+ regulatory T (Treg) cells can undergo both thymic selection and peripheral expansion in response to self peptides that are agonists for their T cell receptors (TCR). However, the specificity by which these TCR must recognize peptide:MHC complexes to activate Treg cell function is not known. We show that CD4+ CD25+ Foxp3+ Treg cells can mediate suppression in response to peptides that are only weakly cross-reactive with the self peptide that induced their formation in vivo. Moreover, suppression could be efficiently activated by peptide analogs that were inefficient at inducing CD69 up-regulation, and that also induced little or no proliferation of naïve CD4+ CD25- Foxp3- T cells expressing the same TCR. These findings provide evidence that self peptide-specific CD4+ CD25+ Foxp3+ Treg cells can exert regulatory function in response to self- and/or pathogen-derived peptides with which they are only weakly cross-reactive.