Downloaded from http://cshperspectives.cshlp.org/ on September 30, 2021 - Published by Cold Spring Harbor Laboratory Press Innate Lymphoid Cells (ILCs): Cytokine Hubs Regulating Immunity and Tissue Homeostasis Maho Nagasawa, Hergen Spits, and Xavier Romero Ros Department of Experimental Immunology, Academic Medical Center at the University of Amsterdam, 1105 BA Amsterdam, Netherlands Correspondence: [email protected] Innate lymphoid cells (ILCs) have emerged as an expanding family of effector cells particu- larly enriched in the mucosal barriers. ILCs are promptly activated by stress signals and multiple epithelial- and myeloid-cell-derived cytokines. In response, ILCs rapidly secrete effector cytokines, which allow them to survey and maintain the mucosal integrity. Uncontrolled action of ILCs might contribute to tissue damage, chronic inflammation, met- abolic diseases, autoimmunity, and cancer. Here we discuss the recent advances in our understanding of the cytokine network that modulate ILC immune responses: stimulating cytokines, signature cytokines secreted by ILC subsets, autocrine cytokines, and cytokines that induce cell plasticity. nnate lymphoid cells (ILCs) are innate lym- Klose et al. 2014; Gasteiger et al. 2015). ILCs Iphocytes that play important roles in immune cross talk with the resident tissue by sensing defense against microbes, regulation of adaptive the cytokines present in their microenviron- immunity, tissue remodeling, and repair and ments and subsequently secreting a plethora homeostasis of hematopoietic and nonhemato- of cytokines that regulate innate immunity poietic cell types. ILCs are present in all tissues, and homeostasis of hematopoietic and nonhe- but they are particularly enriched in mucosal matopoietic cells in the tissues (Artis and Spits surfaces. Unlike adaptive lymphocytes, ILCs 2015). ILC dysregulation contributes to several do not possess rearranged antigen-specific cell pathological conditions, such as inflammatory receptors (T-cell receptor [TCR] or B-cell re- bowel disease (IBD), chronic obstructive pul- ceptor [BCR]), but they mirror T helper (Th) monary disease (COPD), asthma, psoriasis, cell diversity regarding the secretion of signa- and atopic dermatitis (Artis and Spits 2015; ture cytokines and key transcription factors that Eberl et al. 2015). In this review, we will focus regulate their differentiation and functions on the noncytotoxic ILC subsets, which are also (Spits et al. 2013). ILCs develop from the com- termed as helper ILCs. We discuss the cytokines mon lymphoid progenitor (CLP) early in life that influence ILC biology and the role of effec- and seed various tissues to become tissue- tor cytokines produced by ILCs in health and resident lymphocytes (Diefenbach et al. 2014; disease. Editors: Warren J. Leonard and Robert D. Schreiber Additional Perspectives on Cytokines available at www.cshperspectives.org Copyright © 2017 Cold Spring Harbor Laboratory Press; all rights reserved Advanced Online Article. Cite this article as Cold Spring Harb Perspect Biol doi: 10.1101/cshperspect.a030304 1 Downloaded from http://cshperspectives.cshlp.org/ on September 30, 2021 - Published by Cold Spring Harbor Laboratory Press M. Nagasawa et al. ILC FAMILY AND SUBSETS ly produce type 2 cytokines (IL-5, IL-4, IL-9, and IL-13) in response to IL-33, IL-25, and thymic All ILCs express the common cytokine receptor stromal lymphopoietin (TSLP) and rely on γ chain (γc) together with interleukin (IL)-7 re- GATA3 as their key transactional factor; group ceptor (R)α (IL-7Rα, also called CD127), where- 3 ILCs include ILC3s and lymphoid tissue induc- as killer ILCs, natural killer (NK) cells, and intra- er (LTi) cells endowed with the ability to secrete epithelial (ie) ILC1s, lack the expression of IL-7R IL-17 and IL-22 in response to IL-1β and IL-23, but instead express IL-2Rβ (also known as and are functionally dependent on the transcrip- CD122) (Artis and Spits 2015; Eberl et al. tion factor RAR-related orphan receptor γt 2015). ILCs are divided into three groups based (RORγt). on the expression of specific transcription factors and cell-surface molecules as well as their ability to secrete key cytokines (Table 1). Group 1 ILCs CYTOKINES REQUIRED FOR ILC DEVELOPMENT AND MAINTENANCE comprising NKcellsandILC1s produceinterfer- on (IFN)-γ in response to IL-12 and are depen- ILC ontogeny has been intensively studied par- dent on T-bet; group2 ILCs(ILC2s) preferential- ticularly in mouse (Fig. 1). ILCs differentiate Table 1. Mouse and human innate lymphoid cell (ILC) phenotypes Mouse Human Group Progenitor Cell-surface molecules TFs Cell-surface molecules TFs Cytokines 1 cNK CD122, CD49b, NK1.1, EOMES CD122, NKG2A, NKp46, EOMES IFN-γ, − NKG2A, NKp46, T-bet NKp44+/ , IL-12RB1, T-bet TNF IL-12RB1, CD25, CD25, KLRG1 KLRG1 ieILC1 CD122, CD90, NK1.1, EOMES CD122, NKG2A, NKp46, EOMES IFN-γ NKG2A, NKp46, T-bet NKp44, IL-12RB1 T-bet IL-12RB1 ILC1 CD127, CD122, CD90, T-bet CD127, CD161, T-bet IFN-γ, CD49a, NK1.1, NKp46, IL-12RB1, KLRG1, TNF − IL-12RB1 ICOS, CD4+/ 2 ILC2 CD127, CD90, CRTH2, GATA3 CD127, CD161, CRTH2, GATA3 IL-4, IL-5, − − CD117+/ , CD25, ST2, CD117+/ , CD25, ST2, IL-9, TSLPR, IL-17RB, TSLPR, IL17RB, IL-13 KLRG1, ICOS, MHCII KLRG1, ICOS, CCR6, MHCII 3 ILC3 NCR+ CD127, CD90, CD117, RORγt CD127, CD161, CD117, RORγt IL-22 NKp46, CD25, ICOS, T-bet NKp46, NKp44, IL-23R, L-1R1 IL-12RB1, CD25, ICOS, CCR6, IL-23R, IL-1R1, MHCII − ILC3 NCR CD127, CD90, CD25, RORγt CD127, CD161, CD117, RORγt IL-17A ICOS, IL-23R, IL-1R1, T-bet IL-12RB1, CD25, ICOS, MHCII CCR6, IL-23R, IL-1R1 LTi CD127, CD90, CD117, RORγt CD127, CD161, CD117, RORγt IL-17A, CD25, CCR6, IL-23R, CD25, CCR6, IL-23R, IL-22 IL-1R1, MCHII, IL-1R1, NRP1 − CD4+/ , NRP1 ICOS, Inducible T-cell costimulator; KLRG1, killer cell lectin-like receptor subfamily G member 1; NCR, natural cytotoxicity receptor; GATA3, GATA-binding factor 3; EOMES, eomesodermin; TSLPR, thymic stromal lymphopoietin receptor; TFs; transcription factors; IFN, interferon; TNF, tumor necrosis factor; IL, interleukin; RORγt, RAR-related orphan receptor γt. 2 Advanced Online Article. Cite this article as Cold Spring Harb Perspect Biol doi: 10.1101/cshperspect.a030304 Downloaded from http://cshperspectives.cshlp.org/ on September 30, 2021 - Published by Cold Spring Harbor Laboratory Press Innate Lymphoid Cells as Cytokine Hubs α-LPs EILP IL-15 CLP IL-7 NKp cNK CHILP ILCP IL-15 Mouse PLZF+ Human IL-7 ILC1 IL-7 cNK ILC1 ILC2 IL-7 IL-7 IL-7 β IL-15 IL-1 IL-1β ILC2 IL-1β? IL-7 IL-1β α ILC3 IL-7? ILC3 IL-7R ILCP ? IL-2Rβ IL-1R1 CLP LTi LTi Figure 1. Cytokines involved in mouse and human innate lymphoid cells (ILCs) development. All ILCs are derived from a common lymphoid progenitor (CLP). In the mouse, interleukin (IL)-7 is essential for the development of ILC2, ILC3, and lymphoid tissue inducer (LTi) cells, and IL-15 is required for development of natural killer (NK) cells. IL-15 is important for ILC1 development but some ILC1 can develop independent of IL-15. For humans, IL-7 and IL-15 also play an important role in ILC and NK-cell development, and some studies indicate the involvement of IL-1β as, thus far, identified ILC progenitors (ILCPs) all express its receptor. α-LP, α-Lymphoid progenitor; EILP, early innate lymphoid progenitor; CHILP, common helper- like ILC progenitor; PLZF, promyelocytic leukemia zinc-finger protein; NKp, NK progenitor; cNK, conven- tional NK. from the CLP, which resides in the bone marrow so-called ILC progenitors (ILCPs), which have (Possot et al. 2011; Hoyler et al. 2012). CLPs lost the potential to develop into LTi cells but further develop into progenitors expressing the retain the ability to generate helper ILCs (Con- α4β7 integrin (called α lymphoid progenitors stantinides et al. 2014). ILC development is [α-LPs]) and the early innate lymphoid progen- dependent on the expression of the common itors (EILPs) that are able to produce NK cells cytokine receptor γc, which is shared by the and all helper ILCs but have lost the potential to IL-2, IL-4, IL-7, IL-9, IL-15, and IL-21 receptors differentiate into B and T cells (Yu et al. 2014; (Rochman et al. 2009). IL-7 and IL-15 are the γc Yang et al. 2015). α-LPs and EILPs develop family cytokines that are important for ILC de- into the common helper-like ILC progenitors velopment. NK cells express IL-2/IL-15Rβ chain (CHILPs) able to differentiate into all helper (IL-2Rβ or CD122) and IL-15Rα but not IL-7Rα ILC subsets, including LTi cells, but not into chain (or CD127), and their development and/ NK cells (Klose et al. 2014). The CHILP popu- or maintenance is dependent on IL-15 (Kenne- lation contains a subset of cells expressing pro- dy et al. 2000), whereas all helper ILCs express myelocytic leukemia zinc-finger protein (PLZF), IL-7Rα and particularly ILC2s and ILC3s re- Advanced Online Article. Cite this article as Cold Spring Harb Perspect Biol doi: 10.1101/cshperspect.a030304 3 Downloaded from http://cshperspectives.cshlp.org/ on September 30, 2021 - Published by Cold Spring Harbor Laboratory Press M. Nagasawa et al. quire IL-7 for their development and/or main- 1R1+ ILC precursors were found in the periph- tenance (Moro et al. 2010; Neill et al. 2010; Vo- eral tissues and circulation, which could gener- narbourg et al. 2010; Hoyler et al. 2012). Recent- ate all ILC subsets (Lim et al. 2017). These ILC ly, however, it was reported that functional precursors may be the innate version of naïve T ILC2s and ILC3s are present in the lamina pro- cells that can develop into all Th cell subsets – – pria but not in other organs of Il7ra / mice, under the influence of cytokines.