Anti-tumor CC49-zeta CD4 T cells possess both cytolytic and helper functions

The authors report that the nature of the T-cell-receptor-derived signal in normal CD4(+) T cells can induce interleukin-2 (IL-2) secretion or perfori n-mediated cytolytic activity. Normal human T cells were genetically modifi ed to express the tumor antigen specific chimeric immune receptor, CC49-zet a. The CC49-zeta chimeric immune receptor is comprised of the intracellular signaling domains of the TCR CD3 zeta protein fused to the single chain sc Fv of the humanized CC49 antibody, which binds the pan-adenocarcinoma tumor antigen TAG-72. Patient-specific T cells genetically modified to express t he CC49-zeta receptor have been used in patients with colon cancer. The aut hors report that both CD4 and CD8 T cells expressing the CC49-zeta receptor mediated the major histocompatibility complex-unrestricted lysis of TAG-72 -expressing tumor cells with comparable efficiency. However, although the C C49-zeta receptor mediated target cell lysis, it did not support the produc tion of IL-2, even in the presence of CD28 stimulation. Robust IL-2 secreti on and T-cell proliferation were observed when the same CD4 CC49-zeta T cel ls were stimulated through the CD28 receptor and endogenous T-cell receptor . These results indicate that CD4 T lymphocytes possess the capacity to act as both cytolytic and helper T cells and that this difference in effector function is controlled by the nature of the T-Cell receptor-derived signals .