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.
Publication types
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Research Support, N.I.H., Extramural
MeSH terms
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Animals
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Antigens, CD / genetics
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Antigens, CD / immunology
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Antigens, CD / metabolism
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Antigens, Differentiation, T-Lymphocyte / genetics
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Antigens, Differentiation, T-Lymphocyte / immunology
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Antigens, Differentiation, T-Lymphocyte / metabolism
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CD8-Positive T-Lymphocytes / cytology
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CD8-Positive T-Lymphocytes / immunology*
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CD8-Positive T-Lymphocytes / metabolism
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Cell Differentiation / genetics
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Cell Differentiation / immunology
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Cell Survival / genetics
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Cell Survival / immunology
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Forkhead Box Protein O1
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Forkhead Transcription Factors / genetics
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Forkhead Transcription Factors / immunology*
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Forkhead Transcription Factors / metabolism
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Granzymes / genetics
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Granzymes / immunology
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Granzymes / metabolism
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Hepatocyte Nuclear Factor 1-alpha
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Immunologic Memory / genetics
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Immunologic Memory / immunology*
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Lectins, C-Type / genetics
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Lectins, C-Type / immunology
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Lectins, C-Type / metabolism
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Lymphocyte Activation / genetics
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Lymphocyte Activation / immunology
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Lymphocytic Choriomeningitis / immunology
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Lymphocytic choriomeningitis virus / immunology
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Mice
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Mice, Inbred C57BL
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Mice, Transgenic
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T Cell Transcription Factor 1 / genetics
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T Cell Transcription Factor 1 / immunology
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T Cell Transcription Factor 1 / metabolism
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T-Box Domain Proteins / genetics
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T-Box Domain Proteins / immunology
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T-Box Domain Proteins / metabolism
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Up-Regulation / immunology
Substances
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Antigens, CD
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Antigens, Differentiation, T-Lymphocyte
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CD69 antigen
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Eomes protein, mouse
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Forkhead Box Protein O1
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Forkhead Transcription Factors
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Foxo1 protein, mouse
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Hepatocyte Nuclear Factor 1-alpha
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Hnf1a protein, mouse
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Lectins, C-Type
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T Cell Transcription Factor 1
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T-Box Domain Proteins
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Granzymes