The Journal of Experimental Medicine
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Published online
doi:10.1084/jem.20061681
The Journal of Experimental Medicine, Vol. 204, No. 1, 79-91
The Rockefeller University Press, 0022-1007 $30.00
© Riou et al.
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ARTICLE

 Convergence of TCR and cytokine signaling leads to FOXO3a phosphorylation and drives the survival of CD4+ central memory T cells

Catherine Riou1,2,3, Bader Yassine-Diab1, Julien Van grevenynghe1,3, Roland Somogyi5, Larry D. Greller5, Dominic Gagnon1, Sylvain Gimmig1, Peter Wilkinson1, Yu Shi1, Mark J. Cameron6, Roberto Campos-Gonzalez7, Robert S. Balderas7, David Kelvin6, Rafick-Pierre Sekaly1,2,3,4, and Elias K. Haddad1,2,3,4

1 Laboratoire d'Immunologie, Centre de Recherche, Hôpital Saint-Luc du Centre Hospitalier de l'Université de Montréal (CHUM), Montréal, Québec H2X 1P1, Canada
2 Laboratoire d'Immunologie, Département de Microbiologie et d'Immunologie, Université de Montréal, Montréal, Québec H3T 1J4, Canada
3 Institut national de la santé et de la recherche médicale U743, Centre de Recherche, CHUM, Université de Montréal, Montréal, Québec H2X 1P1, Canada
4 Department of Microbiology and Immunology, McGill University, Montréal, Québec H3A 2B4, Canada
5 Biosystemix, Ltd., Sydenham, Ontario K0H 2T0, Canada
6 Toronto General Research Institute, University Health Network, Toronto, Ontario M5G 2M9, Canada
7 BD Biosciences, San Diego, CA 92121

CORRESPONDENCE Rafick-Pierre Sekaly: rafick-pierre.sekaly{at}umontreal.ca

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.

Abbreviations used: ANOVA, analysis of variance; CCR, CC chemokine receptor; FOXO3a, forkhead box O3a; HRP, horseradish peroxidase; IKK, I{kappa}B 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.


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