Kruppel-like factor 2+ CD4 T cells avert microbiota-induced intestinal inflammation

Tzu Yu Shao; Tony T. Jiang; Joseph Stevens; Abigail E. Russi; Ty D. Troutman; Anas Bernieh; Giang Pham; John J. Erickson; Emily M. Eshleman; Theresa Alenghat; Stephen C. Jameson; Kristin A. Hogquist; Casey T. Weaver; David B. Haslam; Hitesh Deshmukh; Sing Sing Way

doi:10.1016/j.celrep.2023.113323

Kruppel-like factor 2+ CD4 T cells avert microbiota-induced intestinal inflammation

Tzu Yu Shao, Tony T. Jiang, Joseph Stevens, Abigail E. Russi, Ty D. Troutman, Anas Bernieh, Giang Pham, John J. Erickson, Emily M. Eshleman, Theresa Alenghat, Stephen C. Jameson, Kristin A. Hogquist, Casey T. Weaver, David B. Haslam, Hitesh Deshmukh, Sing Sing Way

Research output: Contribution to journal › Article › peer-review

Abstract

Intestinal colonization by antigenically foreign microbes necessitates expanded peripheral immune tolerance. Here we show commensal microbiota prime expansion of CD4 T cells unified by the Kruppel-like factor 2 (KLF2) transcriptional regulator and an essential role for KLF2+ CD4 cells in averting microbiota-driven intestinal inflammation. CD4 cells with commensal specificity in secondary lymphoid organs and intestinal tissues are enriched for KLF2 expression, and distinct from FOXP3+ regulatory T cells or other differentiation lineages. Mice with conditional KLF2 deficiency in T cells develop spontaneous rectal prolapse and intestinal inflammation, phenotypes overturned by eliminating microbiota or reconstituting with donor KLF2+ cells. Activated KLF2+ cells selectively produce IL-10, and eliminating IL-10 overrides their suppressive function in vitro and protection against intestinal inflammation in vivo. Together with reduced KLF2+ CD4 cell accumulation in Crohn's disease, a necessity for the KLF2+ subpopulation of T regulatory type 1 (Tr1) cells in sustaining commensal tolerance is demonstrated.

Original language	English (US)
Article number	113323
Journal	Cell reports
Volume	42
Issue number	11
DOIs	https://doi.org/10.1016/j.celrep.2023.113323
State	Published - Nov 28 2023

Bibliographical note

Publisher Copyright:
© 2023 The Author(s)

Keywords

CD4 T cell
CP: Immunology
Candida albicans
Crohn's disease
Tr1 cell
bacterial flagellin Cbir1
commensal tolerance
inflammatory bowel disease
intestinal inflammation
microbiota

PubMed: MeSH publication types

Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

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10.1016/j.celrep.2023.113323

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Shao, T. Y., Jiang, T. T., Stevens, J., Russi, A. E., Troutman, T. D., Bernieh, A., Pham, G., Erickson, J. J., Eshleman, E. M., Alenghat, T., Jameson, S. C., Hogquist, K. A., Weaver, C. T., Haslam, D. B., Deshmukh, H., & Way, S. S. (2023). Kruppel-like factor 2+ CD4 T cells avert microbiota-induced intestinal inflammation. Cell reports, 42(11), Article 113323. https://doi.org/10.1016/j.celrep.2023.113323

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abstract = "Intestinal colonization by antigenically foreign microbes necessitates expanded peripheral immune tolerance. Here we show commensal microbiota prime expansion of CD4 T cells unified by the Kruppel-like factor 2 (KLF2) transcriptional regulator and an essential role for KLF2+ CD4 cells in averting microbiota-driven intestinal inflammation. CD4 cells with commensal specificity in secondary lymphoid organs and intestinal tissues are enriched for KLF2 expression, and distinct from FOXP3+ regulatory T cells or other differentiation lineages. Mice with conditional KLF2 deficiency in T cells develop spontaneous rectal prolapse and intestinal inflammation, phenotypes overturned by eliminating microbiota or reconstituting with donor KLF2+ cells. Activated KLF2+ cells selectively produce IL-10, and eliminating IL-10 overrides their suppressive function in vitro and protection against intestinal inflammation in vivo. Together with reduced KLF2+ CD4 cell accumulation in Crohn's disease, a necessity for the KLF2+ subpopulation of T regulatory type 1 (Tr1) cells in sustaining commensal tolerance is demonstrated.",

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AU - Shao, Tzu Yu

AU - Jiang, Tony T.

AU - Stevens, Joseph

AU - Russi, Abigail E.

AU - Troutman, Ty D.

AU - Bernieh, Anas

AU - Pham, Giang

AU - Erickson, John J.

AU - Eshleman, Emily M.

AU - Alenghat, Theresa

AU - Jameson, Stephen C.

AU - Hogquist, Kristin A.

AU - Weaver, Casey T.

AU - Haslam, David B.

AU - Deshmukh, Hitesh

AU - Way, Sing Sing

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N2 - Intestinal colonization by antigenically foreign microbes necessitates expanded peripheral immune tolerance. Here we show commensal microbiota prime expansion of CD4 T cells unified by the Kruppel-like factor 2 (KLF2) transcriptional regulator and an essential role for KLF2+ CD4 cells in averting microbiota-driven intestinal inflammation. CD4 cells with commensal specificity in secondary lymphoid organs and intestinal tissues are enriched for KLF2 expression, and distinct from FOXP3+ regulatory T cells or other differentiation lineages. Mice with conditional KLF2 deficiency in T cells develop spontaneous rectal prolapse and intestinal inflammation, phenotypes overturned by eliminating microbiota or reconstituting with donor KLF2+ cells. Activated KLF2+ cells selectively produce IL-10, and eliminating IL-10 overrides their suppressive function in vitro and protection against intestinal inflammation in vivo. Together with reduced KLF2+ CD4 cell accumulation in Crohn's disease, a necessity for the KLF2+ subpopulation of T regulatory type 1 (Tr1) cells in sustaining commensal tolerance is demonstrated.

AB - Intestinal colonization by antigenically foreign microbes necessitates expanded peripheral immune tolerance. Here we show commensal microbiota prime expansion of CD4 T cells unified by the Kruppel-like factor 2 (KLF2) transcriptional regulator and an essential role for KLF2+ CD4 cells in averting microbiota-driven intestinal inflammation. CD4 cells with commensal specificity in secondary lymphoid organs and intestinal tissues are enriched for KLF2 expression, and distinct from FOXP3+ regulatory T cells or other differentiation lineages. Mice with conditional KLF2 deficiency in T cells develop spontaneous rectal prolapse and intestinal inflammation, phenotypes overturned by eliminating microbiota or reconstituting with donor KLF2+ cells. Activated KLF2+ cells selectively produce IL-10, and eliminating IL-10 overrides their suppressive function in vitro and protection against intestinal inflammation in vivo. Together with reduced KLF2+ CD4 cell accumulation in Crohn's disease, a necessity for the KLF2+ subpopulation of T regulatory type 1 (Tr1) cells in sustaining commensal tolerance is demonstrated.

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KW - microbiota

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Kruppel-like factor 2+ CD4 T cells avert microbiota-induced intestinal inflammation

Abstract

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Keywords

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