Redirection of T cell antigen specificity through genetic transfer of supraphysiologic T cell receptors

Gene transfer of T cell receptor (TCR) αβ-chains into T cells is a promising strategy for providing a polyclonal population of T cells with redirected reactivity against tumor-associated and viral antigens. One potential problem with this approach is that TCRs, particularly those that react to tumor-associated antigens, bind to their cognate antigen with very low affinities. There is experimental evidence suggesting that TCR affinity is correlated to functional avidity, and that high-avidity T cells are more effective at clearing viral infections and tumors in murine models. In the setting of TCR gene transfer there are no studies analyzing TCR affinity and its relation to T cell effector function. In order to address this question, we studied an HLA-A*02 restricted, HIV-1 p17Gag77-85 (SL9; SLYNTVATL)-specific TCR and three derived mutants with increased affinities. We found that while we could detect differences in TCR-pMHC off-rates on a cell-based assay, CD8+ T cells transduced with all TCR constructs were able to proliferate to similar levels in response to HIVgag. Strikingly, when stimulated with targets loaded with SL9 the high-affinity TCR-transduced CD8 T cells show enhanced production of cytokines. Finally, when co-cultured with HIV-infected targets, the high affinity TCR-transduced cells are more effective at controlling HIV spread than parental TCR-transduced effectors. These data show that TCRs engineered with antibody-like affinities for antigen can induce a polyfunctional phenotype in CD8+ T cells. These receptors can be introduced into CD8- T cells to generate novel responses. The findings obtained from this work could lay the grounds to improved adoptive T cell transfer therapies for HIV and cancer