The molecular events involved in the establishment and maintenance of CD4+ central memory and effector memory T cells (TCM and TEM, respectively) are poorly understood. In this study, we demonstrate that ex vivo isolated TCM are more resistant to both spontaneous and Fas-induced apoptosis than TEM 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+ TCM depends, at least in part, on the activation and phosphorylation of signal transducer and activator of transcription 5a (STAT5a) and forkhead box O3a (FOXO3a). TCM showed a significant increase in the levels of phosphorylation of STAT5a compared with TEM 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 TCM express higher levels of the transcriptionally inactive phosphorylated forms of FOXO3a and concomitantly lower levels of the proapoptotic FOXO3a target, Bim. Experiments aimed at blocking FOXO3a phosphorylation confirmed the role of this phosphoprotein in protecting TCM from apoptosis. Our results provide, for the first time in humans, an insight into molecular mechanisms that could be responsible for the longevity and persistence of CD4+ TCM.
Convergence of TCR and cytokine signaling leads to FOXO3a phosphorylation and drives the survival of CD4+ central memory T cells
Abbreviations used: ANOVA, analysis of variance; CCR, CC chemokine receptor; FOXO3a, forkhead box O3a; HRP, horseradish peroxidase; IKK, IκB kinase; mDC, mature DC; MFI, mean fluorescence intensity; PCA, principal component analysis; SEA, staphylococcal enterotoxin superantigen; TCM, TEM, and TTM, central memory, effector memory, and transitory memory T cell(s), respectively.
Catherine Riou, Bader Yassine-Diab, Julien Van grevenynghe, Roland Somogyi, Larry D. Greller, Dominic Gagnon, Sylvain Gimmig, Peter Wilkinson, Yu Shi, Mark J. Cameron, Roberto Campos-Gonzalez, Robert S. Balderas, David Kelvin, Rafick-Pierre Sekaly, Elias K. Haddad; Convergence of TCR and cytokine signaling leads to FOXO3a phosphorylation and drives the survival of CD4+ central memory T cells . J Exp Med 22 January 2007; 204 (1): 79–91. doi: https://doi.org/10.1084/jem.20061681
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