Anti-Tumor CC49-ζ CD4 T Cells Possess Both Cytolytic and Helper Functions

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Abstract
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 perforin-mediated cytolytic activity. Normal human T cells were genetically modified to express the tumor antigen specific chimeric immune receptor, CC49-ζ. The CC49-ζ chimeric immune receptor is comprised of the intracellular signaling domains of the TCR CD3ζ protein fused to the single chain scFv of the humanized CC49 antibody, which binds the pan-adenocarcinoma tumor antigen TAG-72. Patient-specific T cells genetically modified to express the CC49-ζ receptor have been used in patients with colon cancer. The authors report that both CD4 and CD8 T cells expressing the CC49-ζ receptor mediated the major histocompatibility complex–unrestricted lysis of TAG-72–expressing tumor cells with comparable efficiency. However, although the CC49-ζ receptor mediated target cell lysis, it did not support the production of IL-2, even in the presence of CD28 stimulation. Robust IL-2 secretion and T-cell proliferation were observed when the same CD4 CC49-ζ T cells 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.