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.
authors.affiliation: Division of Gastroenterology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
authors.forename: Matthew R
authors.initials: MR
authors.lastname: Hepworth
authors.forename: Laurel A
authors.initials: LA
authors.lastname: Monticelli
authors.forename: Thomas C
authors.initials: TC
authors.lastname: Fung
authors.forename: Carly G K
authors.initials: CG
authors.lastname: Ziegler
authors.forename: Stephanie
authors.initials: S
authors.lastname: Grunberg
authors.forename: Rohini
authors.initials: R
authors.lastname: Sinha
authors.forename: Adriana R
authors.initials: AR
authors.lastname: Mantegazza
authors.forename: Hak-Ling
authors.initials: HL
authors.lastname: Ma
authors.forename: Alison
authors.initials: A
authors.lastname: Crawford
authors.forename: Jill M
authors.initials: JM
authors.lastname: Angelosanto
authors.forename: E John
authors.initials: EJ
authors.lastname: Wherry
authors.forename: Pandelakis A
authors.initials: PA
authors.lastname: Koni
authors.forename: Frederic D
authors.initials: FD
authors.lastname: Bushman
authors.forename: Charles O
authors.initials: CO
authors.lastname: Elson
authors.forename: Gérard
authors.initials: G
authors.lastname: Eberl
authors.forename: David
authors.initials: D
authors.lastname: Artis
authors.forename: Gregory F
authors.initials: GF
authors.lastname: Sonnenberg
mesh_terms: D000818:Animals; D017951:Antigen Presentation / Q000276:immunology; D001419:Bacteria / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000166:cytology / Q000276:immunology* / Q000473:pathology; D049109:Cell Proliferation; D000949:Histocompatibility Antigens Class II / Q000276:immunology / Q000378:metabolism; D006801:Humans; D007113:Immunity, Innate / Q000276:immunology*; D007249:Inflammation / Q000473:pathology; D020381:Interleukin-17 / Q000378:metabolism; D053759:Interleukin-23 / Q000378:metabolism; D007378:Interleukins / Q000378:metabolism; D007422:Intestines / Q000276:immunology* / Q000382:microbiology* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000378:metabolism; D013559:Symbiosis; D000097043:Interleukin-22
chemical_list: D000949:Histocompatibility Antigens Class II; D020381:Interleukin-17; D053759:Interleukin-23; D007378:Interleukins; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D000097043:Interleukin-22