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

Abstract

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).