Interleukin-2 receptor common γ-chain signaling cytokines regulate activated T cell apoptosis in response to growth factor withdrawal: Selective induction of anti-apoptotic (bcl-2, bcl-xL) but not pro-apoptotic (bax,bcl-xS) gene expression

Cytokine deprivation from activated T cells leads to apoptosis associated with down-regulation of the bcl-2 gene product. It is not clear, however, how cytokines other than interleukin-2 (IL-2) may affect this process and regulate the involvement of other apoptosis-modulating genes. We show that a group of cytokines including IL-2, IL-4, IL-7 and IL-15, which can all signal through the γ chain of the IL-2R (IL-2Rγ), prevent the apoptosis of IL-2-deprived activated T cells. This rescue involves the induction of the anti-apoptosis genes (bcl-2 and bcl-x_L), but causes little change in expression of bax and bcl-x_S, which promote apoptosis. Furthermore, the prevention of apoptosis and induction of proliferation by the common γ chain cytokines can be dissociated. Thus, when proliferation is blocked, the common γ chain cytokines still induce up-regulation of bcl-2 relative to bax and retard apoptosis. These cytokines can thus regulate the persistence or removal of effector T cells by coordinating the balance between genes which promote and those which inhibit apoptosis, events which are probably mediated at least in part by signals through the common γ chain. These data also implicate inappropriate T cell apoptosis resulting from a dysfunctional common γ-chain as part of the pathophysiological defect in patients with X-linked severe-combined immunodeficiency (SCID).