Abstract

Innate lymphoid cells (ILCs) are a newly identified subset of innate cells that play fundamentally crucial roles for early immune defense at mucosal and non-mucosal sites. ILCs consist of ILC1s, ILC2s and ILC3s, which each have distinct transcription factors controlling their development and function. Interestingly, each of the ILC subsets represents the innate counterparts of CD4 + helper T-cell subsets T h1 , T h2 and T h17 on the basis of transcriptional regulation. ILC1s that produce IFN-γ or TNF-α, ILC2s that produce T h2 -type cytokines mainly such as IL-5 or IL-13 and ILC3s have been recently reported and reviewed in terms of IL-22- or IL-17-producing function and cell development. However, in this relatively new field, it remains likely that additional functional and regulatory mechanisms remain to be explored. More recent findings show that ILC3s are regulated by RORγt, which plays an important role for the mucosal barrier and surface protection against pathogenic bacterial infection. ILC3s might cooperate with other cells (e.g. T cells or dendritic cells) directly or indirectly, and subsequently ILC3s have impact on tissues with prompt regulation. Especially, ILC3s in mucosal site are well known to protect the intestinal surface barrier through inducible anti-microbial peptides via IL-22. Here, I will summarize and discuss the roles, function and heterogeneity of ILC3s in mucosal tissues.

Introduction

Recent work has identified new mechanisms of regulation in the development and function of the innate lymphoid cell (ILC) lineage. Since the discovery and definition of helper T-cell subset 1 (T h1 ) and T h2 as distinct helper T-cell lineages responsible for specific cytokine production in 1986 ( 1 ), work has focused on elucidating the specific transcriptional regulation of development pathways of naive T cells into each of the helper T-cell subsets (i.e. T h1 , T h2 or T h17 ) ( Fig. 1 ) and into regulatory T cells.

Fig. 1.

Comparison of helper T cells and their counterpart ILCs with regard to transcriptional regulation. T-bet is required for T h1 and ILC1 development, and both produce IFN-γ. In contrast, IFN-γ-producing cNK cells are regulated by Eomes with T-bet and are differentiated from pre-NK cells. ILC2s mainly produce IL-5 and IL-13 after being stimulated by IL-33, although ILC2s also capable of producing IL-4 and IL-9. There are no reports of IL-6 secretion from ILC2s. Similarly, T h2 cells are well known to produce IL-4, IL-5, IL-6 and IL-13 under activation. IL-17 and IL-22 are regulated by RORγt for cell differentiation in T h17 and ILC3s. T-bet and AhR are also required for NKp46-expressing ILC3s.

Fig. 1.

Comparison of helper T cells and their counterpart ILCs with regard to transcriptional regulation. T-bet is required for T h1 and ILC1 development, and both produce IFN-γ. In contrast, IFN-γ-producing cNK cells are regulated by Eomes with T-bet and are differentiated from pre-NK cells. ILC2s mainly produce IL-5 and IL-13 after being stimulated by IL-33, although ILC2s also capable of producing IL-4 and IL-9. There are no reports of IL-6 secretion from ILC2s. Similarly, T h2 cells are well known to produce IL-4, IL-5, IL-6 and IL-13 under activation. IL-17 and IL-22 are regulated by RORγt for cell differentiation in T h17 and ILC3s. T-bet and AhR are also required for NKp46-expressing ILC3s.

It has only been in recent years that additional novel ILCs important for regulating immune reactions have been discovered. Fundamentally, helper T cells require several signals, such as the T-cell receptor signal via antigen-presenting cells, to gain their functional role, whereas innate cells, including dendritic cells (DCs), can respond to foreign antigens to facilitate swift removal of invading pathogens: a crucial aspect of innate immunity. It was previously assumed that ILCs, especially NK cells, could be considered as the innate counterparts of cytotoxic T cells, sharing the same lineage. Interestingly, the current understanding of ILC subsets is that they instead resemble helper T cells, with respect to cell lineage and developmental regulation by cytokine production as innate helper T-cell counterparts ( Fig. 1 ). In recent years, there has been dramatic progress in understanding the complexity of transcriptional regulation within the newly identified ILC subsets.

Developmental pathways of ILCs

ILC subsets are highly complex populations of immune cells that can be categorized into three major subsets—ILC1s, ILC2s and ILC3s—according to cell lineage and function. Even so, all ILCs can be differentiated from the same common lymphoid progenitor (CLP) regulated by the transcription factors Id2 and NFIL3; the immature ILCs also express CD127 (known as IL-7Rα) and the integrin α4β7 on the cell surface ( 2 , 3 ).

Group 1 ILCs (ILC1s), which include conventional NK (cNK) cells, were initially defined in mouse and human studies by their capacity to produce IFN-γ ( 4 ). In addition, both ILC1s including cNK cells were activated by IL-12 and IL-18. However, further research indicated that eomesodermin (Eomes)-dependent NK cells differ from ILC1s, which are regulated by T-bet and capable of producing both IFN-γ and TNF-α ( 5 ). As such, ILC1s are now thought to be involved in cytokine signaling with less, or no, cytotoxic activity compared with cNK cells. Although IFN-γ is a representative cytokine of both ILC1s and cNK cells, ILC1s are more proficient at TNF-α production. Thus, these IFN-γ-producing ILC1s may play complementary or distinct roles in immune regulatory activity. Further study will be needed to characterize the relationship between cNK cells and ILC1s in response to viruses or in functions dedicated to combating tumors.

Group 2 ILCs (ILC2s) were initially reported as cells that produce T h2 -type cytokines (e.g. IL-5 and IL-13) that are associated with allergic or infectious responses. ILC2s are dependent on the GATA-3, RORα, TCF-1 and Notch transcription factors for their development, conserving the surface markers CD127, CD90 (also known as Thy1) and IL-33R ( 6–8 ). The current understanding is that tissue signaling during parasite infection, tissue injury or allergen sensitization affects stromal cell, mast cell or macrophage production of IL-33, which is a critical cytokine for ILC2 induction. Thus, ILC2 induction by cytokine signaling pathways, especially IL-33, can be considered a surveillance pathway for tissue damage important for maintaining homeostasis.

Group 3 ILCs (ILC3s) are composed of at least three different subtypes, including CCR6-expressing lymphoid-tissue inducer (LTi) ILC3s, NKp46-expressing (NKp46) ILC3s and CCR6 NKp46 double-negative (DN) ILC3s; all three subtypes are regulated by the transcription factor RORγt and activated by IL-23 and/or IL-1β stimulation to produce IL-22 or IL-17. ILC3s can be differentiated from the same lineage-negative (Lin ) CD127 + Flt3 + α4β7 + CLP in fetal liver cells as are other ILCs ( 9 , 10 ); however, ILC3s are heterogeneous and highly complex with regard to their development pathways and functional roles compared with other ILC subsets. Thus, more detail of ILC3 differentiation and function will be discussed below.

Differentiation and composition of ILC3s

ILC3s were initially identified as unique innate cells, distinct from cNK cells, localized in the small intestine that express NKp46 and RORγt ( 11 , 12 ). Recently, it has been shown that all RORγt + ILC3s show a mature phenotype, which express NKp46 on cell surface, and can produce large amount of cytokines such as IL-22. In addition, expression of the transcription factor RORγt is induced for cell differentiation after Id2 and GATA-3 activation ( 13 ).

RORγt was initially described in CD4 + CD8 + thymocytes during cell development ( 14 ) but was also more recently shown to be expressed by fetal CD3 CD4 + CD127 + CD45 + cells in mice, which are known as LTi cells. Here, RORγt was demonstrated to be required for the generation and initiation of gut-associated lymphoid tissue (GALT) development ( 15 ). In T h 17 cells, which also require RORγt for development, RORγt expression is induced in the naive T cells through the activation of Stat3 by cytokine signals such as IL-6 and IL-23, in the presence of TGF-β ( 16 , 17 ). However, Stat3 is not required for the generation of ILC3s, with Stat3 knockout mice displaying normal lymph node (LN) and Peyer’s patch (PP) development ( 18 ), suggesting that lineage-specific transcription factors are differentially induced for the development of different cell subsets. Conversely, cytokine signaling through Stat3 is involved in the functional plasticity of ILC3s. Interestingly, loss of RORγt expression in ILC3s up-regulates T-bet and IFN-γ expression ( 2 ).

Subsequently, the requirement of aryl hydrocarbon receptor (AhR) in cooperating with RORγt for ILC3 development was discovered ( 19–21 ). AhR is a transcription factor activated by several ligands, such as naturally occurring compounds including dietary carotenoids ( 22 ). Although AhR is known to be ubiquitously expressed in tissues and cells of humans, studies in mice lacking AhR showed that cryptopatches and isolated lymphoid follicles (ILFs) in particular were highly disorganized ( 19–21 ), whereas LNs and PPs showed normal development. It is generally believed that LNs and PPs are generated between embryonic days E13.5 and E15.5 ( 23 , 24 ) in mice, whereas the function of cryptopatches and ILFs occurs following birth. Therefore, AhR might have impact on LTi-ILC3s, and other subtypes of ILC3s, at distinct developmental stages after birth. Indeed, AhR-deficient mice that are given a diet free of AhR ligands showed relatively normal numbers of ILC3s at birth ( 19–21 ).

Another transcription factor, promyeloid leukemia zinc finger (PLZF; encoded by Zbtb16 ), which was initially found as an important factor for T-cell and NKT-cell maturation, was shown to be required for ILC differentiation ( 25 ). The role for PLZF in ILC differentiation was demonstrated using Zbtb16cre/GFP mice. However, Zbtb16 -deficient mice do not show expected defects but have defects partially in ILC1 and ILC2 development. Therefore, it is thought to be required for the generation of common ILC precursors from CLP, although more details of regulation mechanisms by PLZF are still unclear.

Chemokine receptors are known to play a role in the organogenesis function of LTi cells. However, analysis of CCR6 ablation showed little effect on the generation of GALT, though the number of cryptopatches was reduced in CCR6-deficient mice. CCR6, along with CD4, is used as a specific marker to differentiate LTi-cell subsets, which can differ in lymphoid tissues depending on the tissue and age of the mice. Recent global gene expression analysis showed that both CD4 + and CD4 LTi cells have overlapped gene profiles ( 26 ). Results in this report further indicated that the selective up-regulation of Nrp1 (known as co-receptor for several ligands including TGF-β1 and semaphorins) is found in CD4 + and CD4 LTi cells ( 26 ). The role of CD4 on LTi cells remains unclear; however, it is known that normal lymphoid tissues are able to form in CD4-deficient mice, suggesting that it might not play a crucial functional role in these cells. CCR6 expression on LTi cells is negatively regulated by T-bet expression ( 2 ) and can be used to distinguish between the different ILC3 subsets; i.e. ILC3s can be classified as CCR6 + ILC3s or CCR6 ILC3s.

CCR6 ILC3s form a subtype comprising NKp46 + RORγt + ILC3s known as NKp46-ILC3s. These were originally described as IL-22-producing ILCs and have protective functions for the intestinal surface ( 11 , 27 ). Recently, NKp46-ILC3s were shown by several groups to require the transcription factor T-bet during development via a Notch-dependent pathway ( 2 , 9 ), whereas LTi cells did not ( 2 ). Similarly, the transcription factor TCF-1, which is an important factor for NK- and T-cell differentiation, is required for the further differentiation of ILC2s and the differentiation of ILC3s into NKp46-expressing ILC3s ( 28 ). Further, recent studies indicate that GATA-3 deficiency affected the development of both ILC2s and ILC3s ( 29–31 ). Thus, TCF-1 cooperating with Id2 under GATA-3 regulation plays a critical role for cell-lineage diversification and their survival. TCF-1 and GATA-3 seem to be key transcription factors for all CD127-expressing CLPs. These findings further indicate that the influence of GATA-3 and its associated transcription factors is regulated under networks that depend on the developmental stage of ILC precursors, similar to T-cell development.

As already mentioned, CCR6 and NKp46 on ILC3s can be used as markers to divide the ILC3 subtypes. Interestingly, the existence of two cell lineages, CCR6 + CD127 hi c-kit hi and CCR6 –/lo CD127 low c-kit lo , both require RORγt for development, raising the question of whether these populations give rise to the different ILC3 subtypes under specific transcriptional regulation ( 2 , 32 ). The current understanding of these two cells is that CCR6 + CD127 hi c-kit hi cells can give rise to CCR6 + LTi-ILC3s, whereas CCR6 –/lo CD127 lo c-kit lo cells might differentiate into NKp46-ILC3s or DN-ILC3s ( 2 , 32 ) ( Table 1 ). Indeed, CCR6 + and CCR6 –/lo ILC3s have been revealed to follow distinct transcriptional regulation pathways ( 2 , 33 ). Although both NKp46-ILC3s and DN-ILC3s express T-bet, DN-ILC3s do not require T-bet for cell differentiation and maintenance ( 5 ). Altogether, current data suggest that the gut environment has an impact on T-bet expression, which then regulates IFN-γ and IL-22 expression. These cytokines then exert effects back on the gut environment such as through epithelial barrier maintenance.

Table 1.

The phenotype of mouse group 3 ILCs

ILC3 subsets Other name Surface markers Transcription factors Cytokines References 
CD4-ILC3s LTi cells  CD4 +/− , NKp46 , NK1.1 , CCR6 + , c-kit high , MHC class II + , IL-1R + , IL-23R +  RORγt + , T-bet , GATA-3 low , NFIL3 + , Id2 + IL-17, IL-22 2,31,33,40  
NKp46-ILC3s NK22, NCR22, NKR- LTi, ILC22  CD4 , NKp46 + , NK1.1 +/− , CCR6 , c-kit low , MHC class II , IL-1R + , IL-23R +  RORγt + , T-bet + , GATA-3 low , NFIL3 + , Id2 + IL-22, IFN-γ 11,12,26,50  
DN-ILC3s LTi-like cell, inflamed ILC or no-name  CD4 , NKp46 , NK1.1 , CCR6 +/− , IL-1R + , IL-23R +  RORγt + , T-bet +/− , GATA-3 low , NFIL3 + , Id2 + IL-17, IL-22, IFN-γ 2,5,31,46  
ILC3 subsets Other name Surface markers Transcription factors Cytokines References 
CD4-ILC3s LTi cells  CD4 +/− , NKp46 , NK1.1 , CCR6 + , c-kit high , MHC class II + , IL-1R + , IL-23R +  RORγt + , T-bet , GATA-3 low , NFIL3 + , Id2 + IL-17, IL-22 2,31,33,40  
NKp46-ILC3s NK22, NCR22, NKR- LTi, ILC22  CD4 , NKp46 + , NK1.1 +/− , CCR6 , c-kit low , MHC class II , IL-1R + , IL-23R +  RORγt + , T-bet + , GATA-3 low , NFIL3 + , Id2 + IL-22, IFN-γ 11,12,26,50  
DN-ILC3s LTi-like cell, inflamed ILC or no-name  CD4 , NKp46 , NK1.1 , CCR6 +/− , IL-1R + , IL-23R +  RORγt + , T-bet +/− , GATA-3 low , NFIL3 + , Id2 + IL-17, IL-22, IFN-γ 2,5,31,46  

Specific functions of each ILC3 subtype

ILC3s can be considered specialized innate-cell populations that are expert in handling the complexity of the mucosal immune system. ILC3s can be sub-divided into at least three different populations, each of which is classified by cell-surface markers CCR6 and NKp46, as discussed below. All the sub-groups do, however, share the features of being Lin but expressing RORγt, CD127 and CD90. This section will discuss the specific functions of each sub-group.

CCR6 + NKp46 LTi-ILC3s

LTi cells were initially described as cells that are localized in the cryptopatch region in the intestine and induce lymphoid tissue there. Although the role of LTi cells in relation to organogenesis has been well described, the ability of LTi cells to secrete the cytokines IL-17 and IL-22 was recently discovered ( 34 ). Subsequently, it has been recognized that LTi-ILC3s are important for the regulation of infection and diseases via cytokine signaling, in addition to their key role in organogenesis. For instance, a recent report showed that IL-22 derived from CCR6 + LTi-ILC3s protects directly against intestinal tissue damage seen in graft-versus-host disease ( 35 ). Further, in addition to the protective functions of IL-22, Stat1-dependent IFN-λ production by CCR6 + ILC3s protected the epithelium in response to rotavirus infection ( 36 ). IL-22 derived from LTi-ILC3s, which express CD90 and lymphotoxin α, also plays an important role to induce intestinal fucosylation of the intestinal epithelium in cooperation with lymphotoxin ( 37 , 38 ). Thus, IL-22 production from CCR6 + LTi-ILCs is important for immunity to bacterial infection and for maintaining protective mucosal barrier function.

In addition to IL-22 production by LTi-ILC3s, recent research showed that LTi-ILC3s potentially express high levels of MHC class II, which is involved in lung inflammation in response to Streptococcus pneumonia infection ( 39 ) and Helicobacter hepaticus infection in the large intestine ( 40 ). These reports suggested that a pathway might exist for CD4 + T-cell induction, via MHC class II on LTi-ILC3s in response to commensal bacteria, independent of cytokines ( 41 ). However, the implication of CD4 and MHC class II expression by LTi-ILC3s remains unclear. It could be possible that LTi-ILC3s participate not only in tissue healing and repair via cytokine signaling pathways but also in the induction of adaptive immunity through cell–cell attachment via MHC class II expression.

CCR6 NKp46 + NKp46-ILC3s

NKp46-ILC3s are an abundant population in the small intestine. Here, they contribute to mucosal defense against infection by Citrobacter rodentium ( C. rodentium ) through production of IL-22 ( 11 ). IL-22 enhances gut-barrier function by the induction of anti-microbial peptides (e.g. the RegIII family) via IL-22R activation on intestinal epithelial cells ( 11 ). Mice lacking IL-22 expression are as susceptible to C. rodentium infection as Rag–/– mice deficient in the common γ chain, which lack all of the common γ-chain-dependent cells ( Ragγc–/– mice; e.g. T, B and NK cells, as well as all ILC subsets). However, recombinant IL-22 treatment or NKp46-ILC3 in vivo transfer rescues C. rodentium -infected Ragγc -deficient mice (N. Satoh-Takayama, unpublished data), suggesting the critical importance of IL-22 from NKp46-ILC3s for the early host defense responses. Further, IL-22 from NKp46-ILC3s also has impact on the resistance to injury and bacterial invasion in the dextran sodium sulfate model of colitis ( 42 ). These observations suggest that IL-22 secretion by NKp46-ILC3s plays a critical role for tissue healing and reparative responses of gut epithelial cells.

Since DC-derived IL-23 and/or IL-1β are able to induce IL-22 production from NKp46-ILC3s ( 43 , 44 ), and IL-22 acts on intestinal epithelial cells, it raises questions about the importance of localization of ILC3s in the epithelial and lamina propria compartments. Our recent study indicated that crosstalk between CXCL16 from CX3CR1 + DCs and CXCR6 on NKp46-ILC3s in the lamina propria is critical for IL-22 production and host defense ( 45 ). Indeed, NKp46-ILC3s preferentially localize in the lamina propria region of the small intestine ( 46 ), whereas LTi-ILC3s mainly exist in the lymphoid follicles, such as cryptopaches ( 15 ). Thus, mucosal NKp46-ILC3s may have distinct functions from other ILC3 subsets for early defense, which is mainly enabled by sitting near to the epithelium, where IL-22 can directly exert its effects on maintaining gut-barrier function and preventing invasion by pathogenic bacteria.

In addition to the functional role of IL-22, IFN-γ-producing NKp46-ILC3s, which phenotypically resemble ILC1s, are reported as having a protective function for the epithelial barrier during Salmonella enterica infection ( 2 ). This unique IFN-γ-producing NKp46-ILC3 subset also expresses T-bet, similar to conventional NKp46-ILC3s, but is independent of IL-12 signaling for IFN-γ production ( 2 ). It seems likely that NKp46-ILC3s are developmentally regulated by T-bet and produce IL-22 and IFN-γ and could also be further regulated depending on the microenvironment conditions.

CCR6 –/lo NKp46 DN-ILC3s

DN-ILC3s are a heterogeneous population that possibly includes progenitors of other ILC3s and other cell populations that are CCR6 T-bet –/low ILC3s ( 5 ). DN-ILC3 populations are able to produce IL-17, IFN-γ and/or IL-22 ( 47 ), similar to NKp46-ILC3s, but particularly in the inflamed large intestine in both mice and humans ( 48 , 49 ). Interestingly, these inflammation-associated DN-ILC3s phenotypically resemble LTi-like ILC3s, although co-expression of T-bet is not required for their differentiation.

As described above, CCR6 + LTi-ILC3s and CCR6 NKp46-ILC3s show distinct profiles, although both cells have restricted differentiation potential from the same progenitor. T-bet and NKp46 expression is correlated with cytokine production, whereas the transcription factor RORγt might promote cell diversity in the complex gut environment. It remains unclear as to how diversity among the ILC3s, especially the DN-ILC3s, is generated. Further studies should aim to elucidate the unknown mechanisms that lead to ILC3 diversity. However, it is still interesting that the mucosal restriction and functional role of the ILC3 subsets depend on the commensal bacteria and protect from invasive pathogens including viruses.

Regulation of ILC3s

The roles of cytokines produced by each subtype of ILC3s in several disease models have been revealed by many recent studies. However, less information is available on how ILC3s can themselves be regulated. It is well known that ILC3s are activated by IL-23 produced by CX3CR1 + DCs or macrophages ( 45 ). As mentioned above, CXCL16–CXCR6 crosstalk between CX3CR1 + DCs and NKp46-ILC3s is important for protection of the surface barrier. In addition, activated DCs are implicated in ILC3 positive feedback through signaling via trimeric lymphotoxin and its receptor (LTα1β2–LTβR) to induce anti-microbial proteins ( 50 ). Interestingly, the commensal flora induces the production of IL-25 by intestinal epithelial cells, which negatively regulates IL-17A and IL-22 production by ILC3s ( 46 ). In our study, reduction of NKp46-ILC3s was found in small intestinal lamina propria lymphocytes of germ-free mice ( 11 ). However, the impact of commensal flora for ILC3 induction is still controversial ( 27 ). It seems likely that relationship between commensal flora and activated DCs might involve in the homeostasis of NKp46-ILC3s in mice, although the mechanisms for the induction are still unclear.

A direct pathway for activation of ILC3s has not yet been reported in mouse studies (i.e. no known TLR signaling has been identified in these cells), but stimulation of human ILC3s by microbe-associated molecular patterns has been shown ( 51 ). Therefore, in order to regulate positive feedback against numerous foreign antigens, indirect regulation systems via DCs might be necessary to avoid abnormal ILC3 activation and might be required for the maintenance of gut homeostasis.

Conclusions and future directions

The discovery of ILC subsets and knowledge of their lineage regulation and role in diseases in mice and humans have progressed rapidly since the initial discovery of ILC3s in the small intestine ( 3 ). An interesting point is that the function and transcription factor expression bears resemblance between ‘acquired’ helper T cells and ‘innate’ helper-like cells, therefore suggesting a ‘counterpart system’ in the early response to pathogen infection/invasion. However, details of each ILC subset, especially the cell classification and categorization, remain to be further characterized. Improved understanding of the mechanisms underlying the development and function of all the ILC subsets in both humans and mice should be widely applicable for human disease therapies. Focusing on the functional ILCs, especially mucosa-associated ILCs, may provide new strategic approaches for human diseases related to the gastrointestinal tract.

Acknowledgements

I am grateful to Kendle Masiowski for comments and careful reading of the manuscript, and Hiroshi Ohno in Laboratory for Intestinal Ecosystem at RIKEN. I would like to also thank James P. Di Santo and all of my colleagues from the Unit of Innate Immunity, Department of Immunology in The Pasteur Institute.

Conflict of interest statement: The author declared no conflict of interests.

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