Chronic engagement of the T cell receptor mediates the induction of T lymphocyte unresponsiveness called clonal anergy. The development of such unresponsiveness has been suggested as one of the mechanisms that regulate peripheral tolerance to self‐antigens and hamper the capacity of tumor antigen‐specific T cells to eliminate cancerous cells. In the attempt to enhance the effector function of CD4+ T lymphocytes and their resistance to clonal anergy induction, we have transduced primary T cells with a retroviral vector encoding active p21ras (RasLeu61). Here we show that RasLeu61 elicited TCR‐independent activation of the Ras‐Raf‐ERK pathway and conferred primary T cells with the ability to secrete IL‐2 in response to stimulation with a Ca2+ ionophore alone, without altering antigen‐, CD3/CD28‐ and PMA/ionomycin‐driven IL‐2 secretion and T cell proliferation in vitro. However, chronic engagement of the TCR onthe surface of RasLeu61 T cells still led to an inability of the cells to produce IL‐2 upon restimulation. These results indicate that enforced p21ras functionality enhances primary T cells responses to calcium‐generated signals, but is insufficient to prevent TCR‐driven T cell unresponsiveness and suggest that additional biochemical mechanisms, independent of p21ras, negatively regulate IL‐2 production in unresponsive T cells.
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