Convergence of TCR and cytokine signaling leads to FOXO3a phosphorylation and drives the survival of CD4+ central memory T cells.
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.
Riou
Catherine
C
Laboratoire d'Immunologie, Centre de Recherche, Hôpital Saint-Luc du Centre Hospitalier de l'Université de Montréal (CHUM), Montréal, Québec H2X 1P1, Canada.
Yassine-Diab
Bader
B
Van grevenynghe
Julien
J
Somogyi
Roland
R
Greller
Larry D
LD
Gagnon
Dominic
D
Gimmig
Sylvain
S
Wilkinson
Peter
P
Shi
Yu
Y
Cameron
Mark J
MJ
Campos-Gonzalez
Roberto
R
Balderas
Robert S
RS
Kelvin
David
D
Sekaly
Rafick-Pierre
RP
Haddad
Elias K
EK
D017209:Apoptosis; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D002470:Cell Survival; D003713:Dendritic Cells / Q000276:immunology; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D020869:Gene Expression Profiling; D006801:Humans; D051550:I-kappa B Kinase / Q000037:antagonists & inhibitors; D007156:Immunologic Memory; D066298:In Vitro Techniques; D008213:Lymphocyte Activation; D010641:Phenotype; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism*; D050799:STAT5 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D025521:Tumor Suppressor Proteins; D019014:fas Receptor / Q000378:metabolism
C491901:FAS protein, human; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D011948:Receptors, Antigen, T-Cell; D050799:STAT5 Transcription Factor; C494092:STAT5A protein, human; D025521:Tumor Suppressor Proteins; D019014:fas Receptor; D051057:Proto-Oncogene Proteins c-akt; D051550:I-kappa B Kinase