FOXO3 regulates CD8 T cell memory by T cell-intrinsic mechanisms.

CD8 T cell responses have three phases: expansion, contraction, and memory. Dynamic alterations in proliferation and apoptotic rates control CD8 T cell numbers at each phase, which in turn dictate the magnitude of CD8 T cell memory. Identification of signaling pathways that control CD8 T cell memory...

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Autores principales:	Jeremy A Sullivan, Eui Ho Kim, Erin H Plisch, Stanford L Peng, M Suresh
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2012
Materias:	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
Acceso en línea:	https://doaj.org/article/2974419d1ebe472f9fcf2c67636d5ab9
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spelling	oai:doaj.org-article:2974419d1ebe472f9fcf2c67636d5ab92021-11-18T06:04:45ZFOXO3 regulates CD8 T cell memory by T cell-intrinsic mechanisms.1553-73661553-737410.1371/journal.ppat.1002533https://doaj.org/article/2974419d1ebe472f9fcf2c67636d5ab92012-02-01T00:00:00Zhttps://www.ncbi.nlm.nih.gov/pmc/articles/pmid/22359505/pdf/?tool=EBIhttps://doaj.org/toc/1553-7366https://doaj.org/toc/1553-7374CD8 T cell responses have three phases: expansion, contraction, and memory. Dynamic alterations in proliferation and apoptotic rates control CD8 T cell numbers at each phase, which in turn dictate the magnitude of CD8 T cell memory. Identification of signaling pathways that control CD8 T cell memory is incomplete. The PI3K/Akt signaling pathway controls cell growth in many cell types by modulating the activity of FOXO transcription factors. But the role of FOXOs in regulating CD8 T cell memory remains unknown. We show that phosphorylation of Akt, FOXO and mTOR in CD8 T cells occurs in a dynamic fashion in vivo during an acute viral infection. To elucidate the potentially dynamic role for FOXO3 in regulating homeostasis of activated CD8 T cells in lymphoid and non-lymphoid organs, we infected global and T cell-specific FOXO3-deficient mice with Lymphocytic Choriomeningitis Virus (LCMV). We found that FOXO3 deficiency induced a marked increase in the expansion of effector CD8 T cells, preferentially in the spleen, by T cell-intrinsic mechanisms. Mechanistically, the enhanced accumulation of proliferating CD8 T cells in FOXO3-deficient mice was not attributed to an augmented rate of cell division, but instead was linked to a reduction in cellular apoptosis. These data suggested that FOXO3 might inhibit accumulation of growth factor-deprived proliferating CD8 T cells by reducing their viability. By virtue of greater accumulation of memory precursor effector cells during expansion, the numbers of memory CD8 T cells were strikingly increased in the spleens of both global and T cell-specific FOXO3-deficient mice. The augmented CD8 T cell memory was durable, and FOXO3 deficiency did not perturb any of the qualitative attributes of memory T cells. In summary, we have identified FOXO3 as a critical regulator of CD8 T cell memory, and therapeutic modulation of FOXO3 might enhance vaccine-induced protective immunity against intracellular pathogens.Jeremy A SullivanEui Ho KimErin H PlischStanford L PengM SureshPublic Library of Science (PLoS)articleImmunologic diseases. AllergyRC581-607Biology (General)QH301-705.5ENPLoS Pathogens, Vol 8, Iss 2, p e1002533 (2012)
institution	DOAJ
collection	DOAJ
language	EN
topic	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5
spellingShingle	Immunologic diseases. Allergy RC581-607 Biology (General) QH301-705.5 Jeremy A Sullivan Eui Ho Kim Erin H Plisch Stanford L Peng M Suresh FOXO3 regulates CD8 T cell memory by T cell-intrinsic mechanisms.
description	CD8 T cell responses have three phases: expansion, contraction, and memory. Dynamic alterations in proliferation and apoptotic rates control CD8 T cell numbers at each phase, which in turn dictate the magnitude of CD8 T cell memory. Identification of signaling pathways that control CD8 T cell memory is incomplete. The PI3K/Akt signaling pathway controls cell growth in many cell types by modulating the activity of FOXO transcription factors. But the role of FOXOs in regulating CD8 T cell memory remains unknown. We show that phosphorylation of Akt, FOXO and mTOR in CD8 T cells occurs in a dynamic fashion in vivo during an acute viral infection. To elucidate the potentially dynamic role for FOXO3 in regulating homeostasis of activated CD8 T cells in lymphoid and non-lymphoid organs, we infected global and T cell-specific FOXO3-deficient mice with Lymphocytic Choriomeningitis Virus (LCMV). We found that FOXO3 deficiency induced a marked increase in the expansion of effector CD8 T cells, preferentially in the spleen, by T cell-intrinsic mechanisms. Mechanistically, the enhanced accumulation of proliferating CD8 T cells in FOXO3-deficient mice was not attributed to an augmented rate of cell division, but instead was linked to a reduction in cellular apoptosis. These data suggested that FOXO3 might inhibit accumulation of growth factor-deprived proliferating CD8 T cells by reducing their viability. By virtue of greater accumulation of memory precursor effector cells during expansion, the numbers of memory CD8 T cells were strikingly increased in the spleens of both global and T cell-specific FOXO3-deficient mice. The augmented CD8 T cell memory was durable, and FOXO3 deficiency did not perturb any of the qualitative attributes of memory T cells. In summary, we have identified FOXO3 as a critical regulator of CD8 T cell memory, and therapeutic modulation of FOXO3 might enhance vaccine-induced protective immunity against intracellular pathogens.
format	article
author	Jeremy A Sullivan Eui Ho Kim Erin H Plisch Stanford L Peng M Suresh
author_facet	Jeremy A Sullivan Eui Ho Kim Erin H Plisch Stanford L Peng M Suresh
author_sort	Jeremy A Sullivan
title	FOXO3 regulates CD8 T cell memory by T cell-intrinsic mechanisms.
title_short	FOXO3 regulates CD8 T cell memory by T cell-intrinsic mechanisms.
title_full	FOXO3 regulates CD8 T cell memory by T cell-intrinsic mechanisms.
title_fullStr	FOXO3 regulates CD8 T cell memory by T cell-intrinsic mechanisms.
title_full_unstemmed	FOXO3 regulates CD8 T cell memory by T cell-intrinsic mechanisms.
title_sort	foxo3 regulates cd8 t cell memory by t cell-intrinsic mechanisms.
publisher	Public Library of Science (PLoS)
publishDate	2012
url	https://doaj.org/article/2974419d1ebe472f9fcf2c67636d5ab9
work_keys_str_mv	AT jeremyasullivan foxo3regulatescd8tcellmemorybytcellintrinsicmechanisms AT euihokim foxo3regulatescd8tcellmemorybytcellintrinsicmechanisms AT erinhplisch foxo3regulatescd8tcellmemorybytcellintrinsicmechanisms AT stanfordlpeng foxo3regulatescd8tcellmemorybytcellintrinsicmechanisms AT msuresh foxo3regulatescd8tcellmemorybytcellintrinsicmechanisms
_version_	1718424591254159360

FOXO3 regulates CD8 T cell memory by T cell-intrinsic mechanisms.

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