Interleukin-6 produced by enteric neurons regulates the number and phenotype of microbe-responsive regulatory T cells in the gut

Yiqing Yan; Deepshika Ramanan; Milena Rozenberg; Kelly McGovern; Daniella Rastelli; Brinda Vijaykumar; Omar Yaghi; Tiphaine Voisin; Munir Mosaheb; Isaac Chiu; Shalev Itzkovitz; Meenakshi Rao; Diane Mathis; Christophe Benoist

doi:https://doi.org/10.1016/j.immuni.2021.02.002

Interleukin-6 produced by enteric neurons regulates the number and phenotype of microbe-responsive regulatory T cells in the gut

Yiqing Yan, Deepshika Ramanan, Milena Rozenberg, Kelly McGovern, Daniella Rastelli, Brinda Vijaykumar, Omar Yaghi, Tiphaine Voisin, Munir Mosaheb, Isaac Chiu, Shalev Itzkovitz, Meenakshi Rao, Diane Mathis, Christophe Benoist

Department of Molecular Cell Biology

Weizmann Institute Of Science

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

Abstract

The immune and enteric nervous (ENS) systems monitor the frontier with commensal and pathogenic microbes in the colon. We investigated whether FoxP3+ regulatory T (Treg) cells functionally interact with the ENS. Indeed, microbe-responsive RORγ+ and Helios+ subsets localized in close apposition to nitrergic and peptidergic nerve fibers in the colon lamina propria (LP). Enteric neurons inhibited in vitro Treg (iTreg) differentiation in a cell-contact-independent manner. A screen of neuron-secreted factors revealed a role for interleukin-6 (IL-6) in modulating iTreg formation and their RORγ+ proportion. Colonization of germfree mice with commensals, especially RORγ+ Treg inducers, broadly diminished colon neuronal density. Closing the triangle, conditional ablation of IL-6 in neurons increased total Treg cells but decreased the RORγ+ subset, as did depletion of two ENS neurotransmitters. Our findings suggest a regulatory circuit wherein microbial signals condition neuronal density and activation, thus tuning Treg cell generation and immunological tolerance in the gut.

Original language	English
Pages (from-to)	499-513.e5
Number of pages	21
Journal	Immunity (Cambridge, Mass.)
Volume	54
Issue number	3
DOIs	https://doi.org/10.1016/j.immuni.2021.02.002
State	Published - 9 Mar 2021

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Yan, Y., Ramanan, D., Rozenberg, M., McGovern, K., Rastelli, D., Vijaykumar, B., Yaghi, O., Voisin, T., Mosaheb, M., Chiu, I., Itzkovitz, S., Rao, M., Mathis, D., & Benoist, C. (2021). Interleukin-6 produced by enteric neurons regulates the number and phenotype of microbe-responsive regulatory T cells in the gut. Immunity (Cambridge, Mass.), 54(3), 499-513.e5. https://doi.org/10.1016/j.immuni.2021.02.002

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title = "Interleukin-6 produced by enteric neurons regulates the number and phenotype of microbe-responsive regulatory T cells in the gut",

abstract = "The immune and enteric nervous (ENS) systems monitor the frontier with commensal and pathogenic microbes in the colon. We investigated whether FoxP3+ regulatory T (Treg) cells functionally interact with the ENS. Indeed, microbe-responsive RORγ+ and Helios+ subsets localized in close apposition to nitrergic and peptidergic nerve fibers in the colon lamina propria (LP). Enteric neurons inhibited in vitro Treg (iTreg) differentiation in a cell-contact-independent manner. A screen of neuron-secreted factors revealed a role for interleukin-6 (IL-6) in modulating iTreg formation and their RORγ+ proportion. Colonization of germfree mice with commensals, especially RORγ+ Treg inducers, broadly diminished colon neuronal density. Closing the triangle, conditional ablation of IL-6 in neurons increased total Treg cells but decreased the RORγ+ subset, as did depletion of two ENS neurotransmitters. Our findings suggest a regulatory circuit wherein microbial signals condition neuronal density and activation, thus tuning Treg cell generation and immunological tolerance in the gut.",

author = "Yiqing Yan and Deepshika Ramanan and Milena Rozenberg and Kelly McGovern and Daniella Rastelli and Brinda Vijaykumar and Omar Yaghi and Tiphaine Voisin and Munir Mosaheb and Isaac Chiu and Shalev Itzkovitz and Meenakshi Rao and Diane Mathis and Christophe Benoist",

year = "2021",

month = mar,

day = "9",

doi = "https://doi.org/10.1016/j.immuni.2021.02.002",

language = "الإنجليزيّة",

volume = "54",

pages = "499--513.e5",

journal = "Immunity (Cambridge, Mass.)",

issn = "1074-7613",

publisher = "Cell Press",

number = "3",

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Yan, Y, Ramanan, D, Rozenberg, M, McGovern, K, Rastelli, D, Vijaykumar, B, Yaghi, O, Voisin, T, Mosaheb, M, Chiu, I, Itzkovitz, S, Rao, M, Mathis, D & Benoist, C 2021, 'Interleukin-6 produced by enteric neurons regulates the number and phenotype of microbe-responsive regulatory T cells in the gut', Immunity (Cambridge, Mass.), vol. 54, no. 3, pp. 499-513.e5. https://doi.org/10.1016/j.immuni.2021.02.002

TY - JOUR

T1 - Interleukin-6 produced by enteric neurons regulates the number and phenotype of microbe-responsive regulatory T cells in the gut

AU - Yan, Yiqing

AU - Ramanan, Deepshika

AU - Rozenberg, Milena

AU - McGovern, Kelly

AU - Rastelli, Daniella

AU - Vijaykumar, Brinda

AU - Yaghi, Omar

AU - Voisin, Tiphaine

AU - Mosaheb, Munir

AU - Chiu, Isaac

AU - Itzkovitz, Shalev

AU - Rao, Meenakshi

AU - Mathis, Diane

AU - Benoist, Christophe

PY - 2021/3/9

Y1 - 2021/3/9

N2 - The immune and enteric nervous (ENS) systems monitor the frontier with commensal and pathogenic microbes in the colon. We investigated whether FoxP3+ regulatory T (Treg) cells functionally interact with the ENS. Indeed, microbe-responsive RORγ+ and Helios+ subsets localized in close apposition to nitrergic and peptidergic nerve fibers in the colon lamina propria (LP). Enteric neurons inhibited in vitro Treg (iTreg) differentiation in a cell-contact-independent manner. A screen of neuron-secreted factors revealed a role for interleukin-6 (IL-6) in modulating iTreg formation and their RORγ+ proportion. Colonization of germfree mice with commensals, especially RORγ+ Treg inducers, broadly diminished colon neuronal density. Closing the triangle, conditional ablation of IL-6 in neurons increased total Treg cells but decreased the RORγ+ subset, as did depletion of two ENS neurotransmitters. Our findings suggest a regulatory circuit wherein microbial signals condition neuronal density and activation, thus tuning Treg cell generation and immunological tolerance in the gut.

AB - The immune and enteric nervous (ENS) systems monitor the frontier with commensal and pathogenic microbes in the colon. We investigated whether FoxP3+ regulatory T (Treg) cells functionally interact with the ENS. Indeed, microbe-responsive RORγ+ and Helios+ subsets localized in close apposition to nitrergic and peptidergic nerve fibers in the colon lamina propria (LP). Enteric neurons inhibited in vitro Treg (iTreg) differentiation in a cell-contact-independent manner. A screen of neuron-secreted factors revealed a role for interleukin-6 (IL-6) in modulating iTreg formation and their RORγ+ proportion. Colonization of germfree mice with commensals, especially RORγ+ Treg inducers, broadly diminished colon neuronal density. Closing the triangle, conditional ablation of IL-6 in neurons increased total Treg cells but decreased the RORγ+ subset, as did depletion of two ENS neurotransmitters. Our findings suggest a regulatory circuit wherein microbial signals condition neuronal density and activation, thus tuning Treg cell generation and immunological tolerance in the gut.

U2 - https://doi.org/10.1016/j.immuni.2021.02.002

DO - https://doi.org/10.1016/j.immuni.2021.02.002

M3 - مقالة

C2 - 33691135

SN - 1074-7613

VL - 54

SP - 499-513.e5

JO - Immunity (Cambridge, Mass.)

JF - Immunity (Cambridge, Mass.)

IS - 3

ER -

Interleukin-6 produced by enteric neurons regulates the number and phenotype of microbe-responsive regulatory T cells in the gut

Abstract

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