title: Intrinsic role of FoxO3a in the development of CD8+ T cell memory.
abstract: CD8(+) T cells undergo rapid expansion during infection with intracellular pathogens, which is followed by swift and massive culling of primed CD8(+) T cells. The mechanisms that govern the massive contraction and maintenance of primed CD8(+) T cells are not clear. We show in this study that the transcription factor, FoxO3a, does not influence Ag presentation and the consequent expansion of CD8(+) T cell response during Listeria monocytogenes infection, but plays a key role in the maintenance of memory CD8(+) T cells. The effector function of primed CD8(+) T cells as revealed by cytokine secretion and CD107a degranulation was not influenced by inactivation of FoxO3a. Interestingly, FoxO3a-deficient CD8(+) T cells displayed reduced expression of proapoptotic molecules BIM and PUMA during the various phases of response, and underwent reduced apoptosis in comparison with wild-type cells. A higher number of memory precursor effector cells and memory subsets was detectable in FoxO3a-deficient mice compared with wild-type mice. Furthermore, FoxO3a-deficient memory CD8(+) T cells upon transfer into normal or RAG1-deficient mice displayed enhanced survival. These results suggest that FoxO3a acts in a cell-intrinsic manner to regulate the survival of primed CD8(+) T cells.
authors.affiliation: National Research Council of Canada, Institute for Biological Sciences, Ottawa, Ontario K1A 0R6, Canada.
authors.forename: Fanny
authors.initials: F
authors.lastname: Tzelepis
authors.forename: Julie
authors.initials: J
authors.lastname: Joseph
authors.forename: Elias K
authors.initials: EK
authors.lastname: Haddad
authors.forename: Susanne
authors.initials: S
authors.lastname: Maclean
authors.forename: Renu
authors.initials: R
authors.lastname: Dudani
authors.forename: Fabien
authors.initials: F
authors.lastname: Agenes
authors.forename: Stanford L
authors.initials: SL
authors.lastname: Peng
authors.forename: Rafick-Pierre
authors.initials: RP
authors.lastname: Sekaly
authors.forename: Subash
authors.initials: S
authors.lastname: Sad
mesh_terms: D000818:Animals; D017951:Antigen Presentation; D000942:Antigens, Bacterial / Q000276:immunology; D017209:Apoptosis / Q000276:immunology; D051017:Apoptosis Regulatory Proteins / Q000096:biosynthesis / Q000235:genetics; D000072224:Bcl-2-Like Protein 11; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism; D016207:Cytokines / Q000097:blood; D003602:Cytotoxicity, Immunologic; D005260:Female; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors / Q000172:deficiency / Q000276:immunology*; D018398:Homeodomain Proteins / Q000235:genetics; D007156:Immunologic Memory / Q000276:immunology*; D019041:L-Selectin / Q000096:biosynthesis / Q000235:genetics; D008089:Listeria monocytogenes / Q000276:immunology; D008088:Listeriosis / Q000097:blood / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology*; D016131:Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism; D008222:Lymphokines / Q000378:metabolism; D051907:Lysosomal Membrane Proteins / Q000276:immunology; D008565:Membrane Proteins / Q000096:biosynthesis / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D010047:Ovalbumin / Q000235:genetics / Q000276:immunology; D011518:Proto-Oncogene Proteins / Q000096:biosynthesis / Q000235:genetics; D020395:Receptors, Interleukin-7 / Q000096:biosynthesis / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000096:biosynthesis / Q000235:genetics; D052118:Lysosomal-Associated Membrane Protein 1
chemical_list: D000942:Antigens, Bacterial; D051017:Apoptosis Regulatory Proteins; D000072224:Bcl-2-Like Protein 11; D016207:Cytokines; D000071316:Forkhead Box Protein O3; D051858:Forkhead Transcription Factors; D018398:Homeodomain Proteins; D019041:L-Selectin; D008222:Lymphokines; D051907:Lysosomal Membrane Proteins; D008565:Membrane Proteins; D010047:Ovalbumin; D011518:Proto-Oncogene Proteins; D020395:Receptors, Interleukin-7; D025521:Tumor Suppressor Proteins; C000606776:Bcl2l11 protein, mouse; C474033:FoxO3 protein, mouse; C052255:Lamp1 protein, mouse; D052118:Lysosomal-Associated Membrane Protein 1; C488588:PUMA protein, mouse; C415350:interleukin-7 receptor, alpha chain; C064658:RAG-1 protein