TCR affinity and specificity requirements for human T regulatory cell function

Plesa G, Zheng L, Medvec A, Wilson CB, Robles-Oteiza C, Liddy N, Bennett AD, Gavarret J, Vuidepot A, Zhao Y, Blazar BR, Jakobsen BK, Riley JL. 2012.
Blood. Feb 7. [Epub ahead of print]

We investigated whether TCRs restricted to the more ubiquitously expressed MHC class I molecules could be used to re-direct human Tregs. By utilizing a series of HLA-A2 restricted TCRs that recognize the same peptide-MHC class I complex (pMHC) with affinities varying up to a 3500-fold difference, we observed that TCR affinity had no effect on the ability of the introduced TCRs to confer potent antigen-specific suppressive activity. Surprisingly, we found a naturally occurring, low affinity MHC class I restricted TCR specific for an NY-ESO-1 epitope that was unable to re-direct a functional CD4 T effector response could confer potent antigen-specific suppressive activity when expressed in Tregs and severely impair the expansion of highly functional HIV-1(GAG) specific CD8 T cells expressing a high affinity TCR. Importantly, this suppressive activity was only observed when both antigens were presented by the same cell and no suppression was observed when the target antigens were put in distinct cells. These studies underscore the clinical utility of using MHC class I restricted TCRs to endow Tregs with specificity to control autoimmune disease and highlight the conditions by which this approach would have most therapeutic benefit.