Intrinsic role of FoxO3a in the development of CD8+ T cell memory

• Published in: The Journal of immunology (1950) Vol. 190; no. 3; pp. 1066 - 1075
• Main Authors: Tzelepis, Fanny, Joseph, Julie, Haddad, Elias K, Maclean, Susanne, Dudani, Renu, Agenes, Fabien, Peng, Stanford L, Sekaly, Rafick-Pierre, Sad, Subash
• Format: Journal Article
• Language: English
• Published: United States 01.02.2013
• Subjects: Animals; Antigen Presentation; Antigens, Bacterial - immunology; Apoptosis - immunology; Apoptosis Regulatory Proteins - biosynthesis; Apoptosis Regulatory Proteins - genetics; Bcl-2-Like Protein 11; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; Cytokines - blood; Cytotoxicity, Immunologic; Female; Forkhead Box Protein O3; Forkhead Transcription Factors - deficiency; Forkhead Transcription Factors - immunology; Homeodomain Proteins - genetics; Immunologic Memory - immunology; L-Selectin - biosynthesis; L-Selectin - genetics; Listeria monocytogenes; Listeria monocytogenes - immunology; Listeriosis - blood; Listeriosis - immunology; Lymphocyte Activation - immunology; Lymphocyte Subsets - immunology; Lymphocyte Subsets - metabolism; Lymphokines - metabolism; Lysosomal Membrane Proteins - immunology; Membrane Proteins - biosynthesis; Membrane Proteins - genetics; Mice; Mice, Inbred C57BL; Ovalbumin - genetics; Ovalbumin - immunology; Proto-Oncogene Proteins - biosynthesis; Proto-Oncogene Proteins - genetics; Receptors, Interleukin-7 - biosynthesis; Receptors, Interleukin-7 - genetics; Tumor Suppressor Proteins - biosynthesis; Tumor Suppressor Proteins - genetics
• ISSN: 0022-1767; 1550-6606
• DOI: 10.4049/jimmunol.1200639

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.