Innate lymphoid cells regulate CD4 + T-cell responses to intestinal commensal bacteria

Matthew R. Hepworth, Laurel A. Monticelli, Thomas C. Fung, Carly G.K. Ziegler, Stephanie Grunberg, Rohini Sinha, Adriana R. Mantegazza, Hak Ling Ma, Alison Crawford, Jill M. Angelosanto, E. John Wherry, Pandelakis A. Koni, Frederic D. Bushman, Charles O. Elson, Gérard Eberl, David Artis, Gregory F. Sonnenberg

Research output: Contribution to journalArticle

374 Citations (Scopus)

Abstract

Innate lymphoid cells (ILCs) are a recently characterized family of immune cells that have critical roles in cytokine-mediated regulation of intestinal epithelial cell barrier integrity. Alterations in ILC responses are associated with multiple chronic human diseases, including inflammatory bowel disease, implicating a role for ILCs in disease pathogenesis. Owing to an inability to target ILCs selectively, experimental studies assessing ILC function have predominantly used mice lacking adaptive immune cells. However, in lymphocyte-sufficient hosts ILCs are vastly outnumbered by CD4 + T cells, which express similar profiles of effector cytokines. Therefore, the function of ILCs in the presence of adaptive immunity and their potential to influence adaptive immune cell responses remain unknown. To test this, we used genetic or antibody-mediated depletion strategies to target murine ILCs in the presence of an adaptive immune system. We show that loss of retinoic-acid-receptor-related orphan receptor-γt-positive (RORγt +) ILCs was associated with dysregulated adaptive immune cell responses against commensal bacteria and low-grade systemic inflammation. Remarkably, ILC-mediated regulation of adaptive immune cells occurred independently of interleukin (IL)-17A, IL-22 or IL-23. Genome-wide transcriptional profiling and functional analyses revealed that RORγt + ILCs express major histocompatibility complex class II (MHCII) and can process and present antigen. However, rather than inducing T-cell proliferation, ILCs acted to limit commensal bacteria-specific CD4 + T-cell responses. Consistent with this, selective deletion of MHCII in murine RORγt + ILCs resulted in dysregulated commensal bacteria-dependent CD4 + T-cell responses that promoted spontaneous intestinal inflammation. These data identify that ILCs maintain intestinal homeostasis through MHCII-dependent interactions with CD4+ T cells that limit pathological adaptive immune cell responses to commensal bacteria.

Original languageEnglish (US)
Pages (from-to)113-117
Number of pages5
JournalNature
Volume498
Issue number7452
DOIs
StatePublished - May 24 2013

Fingerprint

Lymphocytes
Bacteria
T-Lymphocytes
Adaptive Immunity
Major Histocompatibility Complex
Cytokines
Inflammation
Interleukin-23
Retinoic Acid Receptors
Interleukin-17
Inflammatory Bowel Diseases
Immune System
Homeostasis
Epithelial Cells
Cell Proliferation
Genome
Antigens
Antibodies

ASJC Scopus subject areas

  • General

Cite this

Hepworth, M. R., Monticelli, L. A., Fung, T. C., Ziegler, C. G. K., Grunberg, S., Sinha, R., ... Sonnenberg, G. F. (2013). Innate lymphoid cells regulate CD4 + T-cell responses to intestinal commensal bacteria. Nature, 498(7452), 113-117. https://doi.org/10.1038/nature12240

Innate lymphoid cells regulate CD4 + T-cell responses to intestinal commensal bacteria. / Hepworth, Matthew R.; Monticelli, Laurel A.; Fung, Thomas C.; Ziegler, Carly G.K.; Grunberg, Stephanie; Sinha, Rohini; Mantegazza, Adriana R.; Ma, Hak Ling; Crawford, Alison; Angelosanto, Jill M.; John Wherry, E.; Koni, Pandelakis A.; Bushman, Frederic D.; Elson, Charles O.; Eberl, Gérard; Artis, David; Sonnenberg, Gregory F.

In: Nature, Vol. 498, No. 7452, 24.05.2013, p. 113-117.

Research output: Contribution to journalArticle

Hepworth, MR, Monticelli, LA, Fung, TC, Ziegler, CGK, Grunberg, S, Sinha, R, Mantegazza, AR, Ma, HL, Crawford, A, Angelosanto, JM, John Wherry, E, Koni, PA, Bushman, FD, Elson, CO, Eberl, G, Artis, D & Sonnenberg, GF 2013, 'Innate lymphoid cells regulate CD4 + T-cell responses to intestinal commensal bacteria', Nature, vol. 498, no. 7452, pp. 113-117. https://doi.org/10.1038/nature12240
Hepworth MR, Monticelli LA, Fung TC, Ziegler CGK, Grunberg S, Sinha R et al. Innate lymphoid cells regulate CD4 + T-cell responses to intestinal commensal bacteria. Nature. 2013 May 24;498(7452):113-117. https://doi.org/10.1038/nature12240
Hepworth, Matthew R. ; Monticelli, Laurel A. ; Fung, Thomas C. ; Ziegler, Carly G.K. ; Grunberg, Stephanie ; Sinha, Rohini ; Mantegazza, Adriana R. ; Ma, Hak Ling ; Crawford, Alison ; Angelosanto, Jill M. ; John Wherry, E. ; Koni, Pandelakis A. ; Bushman, Frederic D. ; Elson, Charles O. ; Eberl, Gérard ; Artis, David ; Sonnenberg, Gregory F. / Innate lymphoid cells regulate CD4 + T-cell responses to intestinal commensal bacteria. In: Nature. 2013 ; Vol. 498, No. 7452. pp. 113-117.
@article{c4b1160675af4adb9ea0ec021bcd448f,
title = "Innate lymphoid cells regulate CD4 + T-cell responses to intestinal commensal bacteria",
abstract = "Innate lymphoid cells (ILCs) are a recently characterized family of immune cells that have critical roles in cytokine-mediated regulation of intestinal epithelial cell barrier integrity. Alterations in ILC responses are associated with multiple chronic human diseases, including inflammatory bowel disease, implicating a role for ILCs in disease pathogenesis. Owing to an inability to target ILCs selectively, experimental studies assessing ILC function have predominantly used mice lacking adaptive immune cells. However, in lymphocyte-sufficient hosts ILCs are vastly outnumbered by CD4 + T cells, which express similar profiles of effector cytokines. Therefore, the function of ILCs in the presence of adaptive immunity and their potential to influence adaptive immune cell responses remain unknown. To test this, we used genetic or antibody-mediated depletion strategies to target murine ILCs in the presence of an adaptive immune system. We show that loss of retinoic-acid-receptor-related orphan receptor-γt-positive (RORγt +) ILCs was associated with dysregulated adaptive immune cell responses against commensal bacteria and low-grade systemic inflammation. Remarkably, ILC-mediated regulation of adaptive immune cells occurred independently of interleukin (IL)-17A, IL-22 or IL-23. Genome-wide transcriptional profiling and functional analyses revealed that RORγt + ILCs express major histocompatibility complex class II (MHCII) and can process and present antigen. However, rather than inducing T-cell proliferation, ILCs acted to limit commensal bacteria-specific CD4 + T-cell responses. Consistent with this, selective deletion of MHCII in murine RORγt + ILCs resulted in dysregulated commensal bacteria-dependent CD4 + T-cell responses that promoted spontaneous intestinal inflammation. These data identify that ILCs maintain intestinal homeostasis through MHCII-dependent interactions with CD4+ T cells that limit pathological adaptive immune cell responses to commensal bacteria.",
author = "Hepworth, {Matthew R.} and Monticelli, {Laurel A.} and Fung, {Thomas C.} and Ziegler, {Carly G.K.} and Stephanie Grunberg and Rohini Sinha and Mantegazza, {Adriana R.} and Ma, {Hak Ling} and Alison Crawford and Angelosanto, {Jill M.} and {John Wherry}, E. and Koni, {Pandelakis A.} and Bushman, {Frederic D.} and Elson, {Charles O.} and G{\'e}rard Eberl and David Artis and Sonnenberg, {Gregory F.}",
year = "2013",
month = "5",
day = "24",
doi = "10.1038/nature12240",
language = "English (US)",
volume = "498",
pages = "113--117",
journal = "Nature",
issn = "0028-0836",
publisher = "Nature Publishing Group",
number = "7452",

}

TY - JOUR

T1 - Innate lymphoid cells regulate CD4 + T-cell responses to intestinal commensal bacteria

AU - Hepworth, Matthew R.

AU - Monticelli, Laurel A.

AU - Fung, Thomas C.

AU - Ziegler, Carly G.K.

AU - Grunberg, Stephanie

AU - Sinha, Rohini

AU - Mantegazza, Adriana R.

AU - Ma, Hak Ling

AU - Crawford, Alison

AU - Angelosanto, Jill M.

AU - John Wherry, E.

AU - Koni, Pandelakis A.

AU - Bushman, Frederic D.

AU - Elson, Charles O.

AU - Eberl, Gérard

AU - Artis, David

AU - Sonnenberg, Gregory F.

PY - 2013/5/24

Y1 - 2013/5/24

N2 - Innate lymphoid cells (ILCs) are a recently characterized family of immune cells that have critical roles in cytokine-mediated regulation of intestinal epithelial cell barrier integrity. Alterations in ILC responses are associated with multiple chronic human diseases, including inflammatory bowel disease, implicating a role for ILCs in disease pathogenesis. Owing to an inability to target ILCs selectively, experimental studies assessing ILC function have predominantly used mice lacking adaptive immune cells. However, in lymphocyte-sufficient hosts ILCs are vastly outnumbered by CD4 + T cells, which express similar profiles of effector cytokines. Therefore, the function of ILCs in the presence of adaptive immunity and their potential to influence adaptive immune cell responses remain unknown. To test this, we used genetic or antibody-mediated depletion strategies to target murine ILCs in the presence of an adaptive immune system. We show that loss of retinoic-acid-receptor-related orphan receptor-γt-positive (RORγt +) ILCs was associated with dysregulated adaptive immune cell responses against commensal bacteria and low-grade systemic inflammation. Remarkably, ILC-mediated regulation of adaptive immune cells occurred independently of interleukin (IL)-17A, IL-22 or IL-23. Genome-wide transcriptional profiling and functional analyses revealed that RORγt + ILCs express major histocompatibility complex class II (MHCII) and can process and present antigen. However, rather than inducing T-cell proliferation, ILCs acted to limit commensal bacteria-specific CD4 + T-cell responses. Consistent with this, selective deletion of MHCII in murine RORγt + ILCs resulted in dysregulated commensal bacteria-dependent CD4 + T-cell responses that promoted spontaneous intestinal inflammation. These data identify that ILCs maintain intestinal homeostasis through MHCII-dependent interactions with CD4+ T cells that limit pathological adaptive immune cell responses to commensal bacteria.

AB - Innate lymphoid cells (ILCs) are a recently characterized family of immune cells that have critical roles in cytokine-mediated regulation of intestinal epithelial cell barrier integrity. Alterations in ILC responses are associated with multiple chronic human diseases, including inflammatory bowel disease, implicating a role for ILCs in disease pathogenesis. Owing to an inability to target ILCs selectively, experimental studies assessing ILC function have predominantly used mice lacking adaptive immune cells. However, in lymphocyte-sufficient hosts ILCs are vastly outnumbered by CD4 + T cells, which express similar profiles of effector cytokines. Therefore, the function of ILCs in the presence of adaptive immunity and their potential to influence adaptive immune cell responses remain unknown. To test this, we used genetic or antibody-mediated depletion strategies to target murine ILCs in the presence of an adaptive immune system. We show that loss of retinoic-acid-receptor-related orphan receptor-γt-positive (RORγt +) ILCs was associated with dysregulated adaptive immune cell responses against commensal bacteria and low-grade systemic inflammation. Remarkably, ILC-mediated regulation of adaptive immune cells occurred independently of interleukin (IL)-17A, IL-22 or IL-23. Genome-wide transcriptional profiling and functional analyses revealed that RORγt + ILCs express major histocompatibility complex class II (MHCII) and can process and present antigen. However, rather than inducing T-cell proliferation, ILCs acted to limit commensal bacteria-specific CD4 + T-cell responses. Consistent with this, selective deletion of MHCII in murine RORγt + ILCs resulted in dysregulated commensal bacteria-dependent CD4 + T-cell responses that promoted spontaneous intestinal inflammation. These data identify that ILCs maintain intestinal homeostasis through MHCII-dependent interactions with CD4+ T cells that limit pathological adaptive immune cell responses to commensal bacteria.

UR - http://www.scopus.com/inward/record.url?scp=84878737123&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84878737123&partnerID=8YFLogxK

U2 - 10.1038/nature12240

DO - 10.1038/nature12240

M3 - Article

C2 - 23698371

AN - SCOPUS:84878737123

VL - 498

SP - 113

EP - 117

JO - Nature

JF - Nature

SN - 0028-0836

IS - 7452

ER -