Supraphysiologic TCRs Generate Polyfunctional CD8 T Cells That Effectively Re‐directed the CD8 T cell Immune Response

We evaluated how increased TCR affinity for its cognate antigen affects its ability to redirect an HIV‐1 and tumor specific immune response. TCRs differing in affinity for the HIVgag epitope SL9 were introduced into primary human CD8 T cells and the ability of these cells to proliferate, produce cytokines, and control HIV infection was studied. Increased avidity did not alter the ability of CD8 T cells to expand in response to antigen stimulation. In contrast, CD8 T cells transduced with high affinity, supraphysiologic SL9 TCRs were more likely to have a polyfunctional cytokine profile following antigen stimulation. The most notable difference was the ability of CD8 T cells transduced with supraphysiologic SL9 TCRs to produce IL‐2, a cytokine whose expression correlates closely with CD8 T cell antiviral activity during the natural progression of HIV‐1 disease. Importantly, high affinity SL9‐specific TCR expressing cells more effectively controlled HIV‐1 infection than cells expressing the wildtype SL9‐specific TCR receptor. This difference was most pronounced when viruses that contained known SL9 escape mutations were used. Similar experiments using hTERT TCRs were performed. These data indicate that engineered TCRs with antibody‐like‐affinities for antigen can induce a polyfunctional phenotype to CD8 T cells and that use of supraphysiologic TCRs in adoptive T cell therapy is attractive.