A CCL1/CCR8-dependent feed-forward mechanism drives ILC2 functions in type 2–mediated inflammation

Abstract

Group 2 innate lymphoid cells (ILC2s) possess indispensable roles during type 2–mediated inflammatory diseases. Although their physiological and detrimental immune functions seem to depend on the anatomical compartment they reside, their tissue tropism and the molecular and immunological processes regulating the self-renewal of the local pool of ILC2s in the context of inflammation or infection are incompletely understood. Here, we analyzed the role of the CC-chemokine receptor CCR8 for the biological functions of ILC2s. In vitro and in vivo experiments indicated that CCR8 is in comparison to the related molecule CCR4 less important for migration of these cells. However, we found that activated mouse and human ILC2s produce the CCR8 ligand CCL1 and are a major source of CCL1 in vivo. CCL1 signaling to ILC2s regulates their proliferation and supports their capacity to protect against helminthic infections. In summary, we identify a novel chemokine receptor–dependent mechanism by which ILC2s are regulated during type 2 responses.

CD4 T Helper Cell Subsets and Related Human Immunological Disorders

“…These cytokines can also be produced by ILC2s (although IL-4 production by ILC2s is somewhat limited), and they work together to eliminate invading pathogens [74]. Th2 cells and ILC2s also express chemokine receptors on the cell surface, including CCR3, CCR4, and CCR8, to receive migration signals from ligands (CCL11 for CCR3, CCL17 and CCL22 for CCR4, and CCL1 for CCR8) secreted by epithelial cells [75][76][77]. In addition to recruiting Th2 cells and ILC2s, these chemokines can also recruit other cells, such as DCs, eosinophils, basophils, and mast cells to the damaged epithelial sites caused by helminth infection or protease allergens [30,78].…”

Regulation of Human Innate Lymphoid Cells in the Context of Mucosal Inflammation

“…In accordance with the latter, association data from patients with rheumatoid arthritis showed an inverse correlation between blood ILC2 counts and disease activity (149). Moreover, the chemokine CCL1 could recently be identified as another autocrine activator of ILC2 function in mice and men, mediating its effects via CCR8 signaling (86).…”

Group 2 Innate Lymphoid Cells (ILC2) Suppress Beneficial Type 1 Immune Responses During Pulmonary Cryptococcosis

“…To further ascertain the functional impact of ILC2 on the immune response to cryptococcal infection, we next adoptively transferred sort-purified and in vitro expanded ILC2s of C57BL/6 mice into C. neoformans infected Tie2 cre Rora flox mice on a C57BL/6 background (27). These ILC2s are able to target the murine lung upon intravenous injection as we have recently shown in a model of type 2 mediated lung inflammation (27,28), albeit rather high numbers of cells are required for effective long term studies.…”

“…To further ascertain the functional impact of ILC2 on the immune response to cryptococcal infection, we next adoptively transferred sort-purified and in vitro expanded ILC2s of C57BL/6 mice into C. neoformans infected Tie2 cre Rora flox mice on a C57BL/6 background (27). These ILC2s are able to target the murine lung upon intravenous injection as we have recently shown in a model of type 2 mediated lung inflammation (27,28), albeit rather high numbers of cells are required for effective long term studies. Strikingly, reconstitution of the ILC2 compartment was found to be associated with significantly increased lung fungal burden at 14 dpi as revealed by cfu determination (Figure 3A) and histological staining compared to controls indicating that the immunomodulatory functions of ILC2s are sufficient to abrogate the protective phenotype in Tie2 cre Rora flox mice ( Figure 3B).…”

“…Tie2 cre Rora flox/sg (C57BL/6 background) were described previously (26,27). Rora Cre tdTomato flox mice were generated by crossbreeding Rora Cre mice [kindly provided by Dennis O'Leary (51)] to ROSA26-LSL-tdTomato mice that contain a transgene encoding an enhanced tandem dimer tomato red fluorescent protein (tdTomato) in the ROSA26 locus with a lox-transcriptional stop-lox cassette inserted between exon 1 and exon 2 (52).…”