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The molecular events involved in the establishment and maintenance of CD4⁺ central memory and effector memory T cells (T_CM and T_EM, respectively) are poorly understood. In this study, we demonstrate that ex vivo isolated T_CM are more resistant to both spontaneous and Fas-induced apoptosis than T_EM and have an increased capacity to proliferate and persist in vitro. Using global gene expression profiling, single cell proteomics, and functional assays, we show that the survival of CD4⁺ T_CM depends, at least in part, on the activation and phosphorylation of signal transducer and activator of transcription 5a (STAT5a) and forkhead box O3a (FOXO3a). T_CM showed a significant increase in the levels of phosphorylation of STAT5a compared with T_EM in response to both IL-2 (P < 0.04) and IL-7 (P < 0.002); the latter is well known for its capacity to enhance T cell survival. Moreover, ex vivo T_CM express higher …