title: Differentiation of CD8 memory T cells depends on Foxo1.
abstract: The forkhead O transcription factors (FOXO) integrate a range of extracellular signals, including growth factor signaling, inflammation, oxidative stress, and nutrient availability, to substantially alter the program of gene expression and modulate cell survival, cell cycle progression, and many yet to be unraveled cell type-specific responses. Naive antigen-specific CD8(+) T cells undergo a rapid expansion and arming of effector function within days of pathogen exposure. In addition, by the peak of expansion, they form precursors to memory T cells capable of self-renewal and indefinite survival. Using lymphocytic choriomeningitis virus Armstrong to probe the response to infection, we found that Foxo1(-/-) CD8(+) T cells expand normally with no defects in effector differentiation, but continue to exhibit characteristics of effector T cells long after antigen clearance. The KLRG1(lo) CD8(+) T cells that are normally enriched for memory-precursor cells retain Granzyme B and CD69 expression, and fail to up-regulate TCF7, EOMES, and other memory signature genes. As a correlate, Foxo1(-/-) CD8(+) T cells were virtually unable to expand upon secondary infection. Collectively, these results demonstrate an intrinsic role for FOXO1 in establishing the post-effector memory program that is essential to forming long-lived memory cells capable of immune reactivation.
authors.affiliation: Molecular Biology Section, Division of Biological Sciences, Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA, USA.
authors.forename: Rodrigo
authors.initials: R
authors.lastname: Hess Michelini
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Doedens
authors.forename: Ananda W
authors.initials: AW
authors.lastname: Goldrath
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Hedrick
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D000945:Antigens, Differentiation, T-Lymphocyte / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000378:metabolism; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002470:Cell Survival / Q000235:genetics / Q000276:immunology; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D053804:Granzymes / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D051538:Hepatocyte Nuclear Factor 1-alpha; D007156:Immunologic Memory / Q000235:genetics / Q000276:immunology*; D037181:Lectins, C-Type / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008213:Lymphocyte Activation / Q000235:genetics / Q000276:immunology; D008216:Lymphocytic Choriomeningitis / Q000276:immunology; D008217:Lymphocytic choriomeningitis virus / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D051822:T Cell Transcription Factor 1 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D020825:T-Box Domain Proteins / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D015854:Up-Regulation / Q000276:immunology; D000099192:CD69 Antigens
chemical_list: D015703:Antigens, CD; D000945:Antigens, Differentiation, T-Lymphocyte; D000071161:Forkhead Box Protein O1; D051858:Forkhead Transcription Factors; D053804:Granzymes; D051538:Hepatocyte Nuclear Factor 1-alpha; D037181:Lectins, C-Type; D051822:T Cell Transcription Factor 1; D020825:T-Box Domain Proteins; D000099192:CD69 Antigens; C491198:Eomes protein, mouse; C467200:Foxo1 protein, mouse; C496488:Hnf1a protein, mouse