Adipose-Resident Group 1 Innate Lymphoid Cells Promote Obesity-Associated Insulin Resistance

Abstract

Innate lymphoid cells (ILCs) function to protect epithelial barriers against pathogens, and maintain tissue homeostasis in both barrier and non-barrier tissues. Here, utilizing Eomes reporter mice, we identify a subset of adipose group 1 ILC (ILC1) and demonstrate a role for these cells in metabolic disease. Adipose ILC1 were dependent on the transcription factors Nfil3 and T-bet, but phenotypically and functionally distinct from adipose mature natural killer (NK) and immature NK cells. Analysis of parabiotic mice revealed that adipose ILC1 maintained long-term tissue residency. Diet-induced obesity drove early production of interleukin (IL)-12 in adipose tissue depots, and led to the selective proliferation and accumulation of adipose-resident ILC1 in a manner dependent on the IL-12 receptor and STAT4. ILC1-derived interferon-γ was necessary and sufficient to drive proinflammatory macrophage polarization to promote obesity-associated insulin resistance. Thus, adipose-resident ILC1 contribute to obesity-related pathology in response to dysregulated local proinflammatory cytokine production.

ILC1 Confer Early Host Protection at Initial Sites of Viral Infection

“…During homeostasis, parabiotic mouse and lineage-tracing experiments have been used to show that liver and adipose NK cells and ILC1 are stable phenotypic and functional lineages (Daussy et al, 2014; O’Sullivan et al, 2016; Peng et al, 2013; Sojka et al, 2014). However, whether differences between NK cells and ILC1 are lost during viral-induced inflammation is unknown.…”

“…However, these studies used T-bet-deficient mice, which have reduced numbers of mature ILC1 and mature NK cells (Deng et al, 2015; O’Sullivan et al, 2016; Townsend et al, 2004), to conclude that intestinal ILC1 are required for host microbial protection. T-bet has also been shown to be required for NK cell IFN-γ production and migration, and the development of NKp46 + ILC3s (Jenne et al, 2009; Rankin et al, 2013; Townsend et al, 2004).…”

“…However, a key challenge is selecting definitive criteria to discriminate NK cells from other group 1 ILCs at steady state and during immune responses. Eomes, CD49a, CD49b, and TRAIL are differentially expressed by each group 1 ILC within different peripheral organs during homeostasis (Cortez et al, 2014; Daussy et al, 2014; Gordon et al, 2012; Klose et al, 2014; O’Sullivan et al, 2016; Sojka et al, 2014), but it is unclear whether these characteristics can be modulated by the activation state of the cells during inflammation, injury, or infection. From our RNA-seq analysis, we identified the markers CD61 and CD200r1 as highly expressed on peripheral tissue-resident ILCs, but either barely or not expressed by circulating NK cells.…”

Re(de)fining Innate Lymphocyte Lineages in the Face of Cancer

“…Although the barrier functions of ILCs have been primarily studied at mucosal surfaces, nonmucosal organs also contain sizable ILC populations. These cells are important for tissue homeostasis, and dysregulation of their activities can result in immunopathology, such as kidney ischemia and obesity (8,9).…”

Innate Lymphoid Cell Immunometabolism

“…In contrast to NK cells, ILC1 lack Eomes and CD49b expression, but express CD49a (α 1 β 1 integrin). ILC1 are long-term tissue resident in peripheral organs, and may be required to protect the host from bacterial infections at barrier sites such as the intestine[5, 6, 9–13]. Group 2 ILCs (ILC2) express the transcription factor GATA3 and produce type 2 cytokines such as IL-4, IL-5, and IL-13, along with the tissue reparative factor amphiregulin, to promote host resistance to helminth infection[14–18].…”