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

By M. Hepworth, L. Monticelli, Thomas C. Fung, Carly G. K. Ziegler, Stephanie Grunberg, Rohini Sinha, Adriana R. Mantegazza, H. Ma, Alison Crawford, Jill M. Angelosanto and 7 more. Nature, 2013

761 citations recorded by the source corpus.

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.

Subfields: Immunology, Surgery

View Paper: https://www.semanticscholar.org/paper/5e68c3f03ab28483084e8e318fd4d61fc0f26ea0

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Citations in the corpus

• Innate Lymphoid Cells: 10 Years On. (2018, neutral): “In addition, ILC3s can regulate adaptive Th17 cell responses (Hepworth et al., 2013).”
• Mining the human gut microbiota for immunomodulatory organisms (2017, neutral): “…immunocyte populations, such as Th2 skewing of their CD4+ T cell compartments; compromised innate lymphoid cell (ILC) function; a deficiency in immunoglobulin A (IgA)-producing plasma cells; and, more generally, greater susceptibility to infection (Surana and Kasper, 2014; Hepworth et al., 2013).”
• Interleukin-22: immunobiology and pathology (2015, background): “Commensal Bacteria Bacterial Intestine Regulates composition of microbiota (262, 391, 394)”
• Homeostatic immunity and the microbiota (2017, neutral): “ILC3 have also been proposed to regulate immune reactivity to the microbiota as MHC-II expressing ILC3 can interact with and delete CD4+ T cells specific for commensal antigens (Hepworth et al., 2015; Hepworth et al., 2013).”
• MHCII-Mediated Dialog between Group 2 Innate Lymphoid Cells and CD4+ T Cells Potentiates Type 2 Immunity and Promotes Parasitic Helminth Expulsion (2014, background): “Notably, ILC2s express the costimulatory molecules CD80 and CD86 on their surface, whereas ILC3s do not (Hepworth et al., 2013), and this might underlie the agonistic role for MHCII on ILC2s.”
• The gut microbiome: Relationships with disease and opportunities for therapy (2018, background): “…fewer T reg cells (Atarashi et al., 2011; Ohnmacht et al., 2015), lack regulatory gut CD4+CD8αα+ double-positive intra-epithelial lymphocytes (Cervantes-Barragan et al., 2017), have compromised innate lymphoid cell function (Hepworth et al., 2013), and are more susceptible to microbial infections.”