Innate lymphoid cells (ILCs) encompass natural killer cells (NK) and ILC1, ILC2, and ILC3 cells (1–3). In contrast to T cells, these cells lack rearranged antigen receptors (1–3). It has been demonstrated that ILCs develop in the fetal liver and adult bone marrow, whereas mature ILCs are mainly enriched in the GI tract, lungs, liver, and skin (1–3). NK cells, which account for ~15% of human peripheral blood (PB) lymphocytes, exert cytolytic effects, and secrete IFN-γ, granzyme B, and perforin. In mouse, NK cells are characterized by the expression of natural killer cell p46-related protein (NKp46; also known as NCR1) receptor, and expressing transcription factors T-bet and Eomes (4–6) (Figure 1, Table 1). In humans, there are two main subsets of NK cells: CD3⁻CD56^brightCD16⁻ and CD3⁻CD56^dim CD16⁺ cells (4–6) (Table 2). ILCs exhibit a cytokine repertoire that mirrors that of T helper cells. For instance, similar to Th1 cells, ILC1 cells can respond to IL-12 and IL-15 and subsequently secrete effector cytokines, such as IFN-γ and TNF-α (4–6). However, unlike NK cells, ILC1 cells do not display cytolytic effects (15). Murine ILC1 cells express Nkp46, NK1.1, T-bet, and CD200r1, but without expression of Eomes (16).

In humans, CD127⁺CD161⁺CD34⁻ c-Kit⁻ T-bet⁺ Eomes⁻IFN-γ⁺ILC1 cells are enriched in the tonsils (15–17). Interestingly, Lin⁻CD127⁺CD161⁺CD117⁻NKp44⁻CRTH2⁻ ILC1 cells have been found in the PBMCs of healthy individuals and atopic dermatitis (AD) patients (15–18).

ILC2 cells are defined as Lin⁻CD127⁺CD25⁺KLRG1⁺ GATA3^high cells in mice. These cells are responsive to multiple cytokines, including IL-2, IL-4, IL-7, IL-25, IL-33, TSLP, and prostaglandin D2, and subsequently produce Th2-type cytokines, such as IL4, IL-5, IL-9, IL-13, and amphiregulin (AREG) (1, 13, 19–26). In humans, ILC2 cells express GATA3, CD127, CD161, CD25, ST-2, IL-17A, and chemo-attractant receptor-homologous molecule expressed on Th2 lymphocytes (CRTH2) (1, 13, 15).

Both murine and human ILC3 cells are identified as Lin⁻CD127⁺RORγt⁺ cells (15). Mouse ILC3 cells consists of three subsets: lymphoid tissue-inducer cells (LTi), LTi-like CCR6-expressing ILC3 cells and NCR-expressing ILC3 cells (NCR⁺ILC3) (1, 15). Similar to Th17 cells, they are poised to respond to the stimulation by IL-1β, IL-6, and IL-23 and subsequently produce effector cytokines, such as IL-22, IL-17A, IL-17F, GM-CSF, TNF-α, and LTα₁β₂ (1, 15, 27–29).

NK cells are critical players in controlling intracellular bacterial and tumor surveillance (1, 15, 30). ILC1 cells are capable of controlling intracellular pathogens, whereas ILC2 cells have the capacity to limit extracellular parasitic worm infections, promote epithelial repair, and maintain mucosal tissue homeostasis. Notably, ILC2 cells are associated with chronic diseases such as pulmonary fibrosis, hepatic fibrosis, and atopic dermatitis (1, 2, 15, 30). NCR⁺ILC3 cells are the most prevalent ILC3 subset in the intestine, whereas LTi-like ILC3 cells are mainly localized in the colon and lymphoid tissues (2, 30–32). ILC3 cells are key contributors to tissue repair and protect mucosal barriers against infection by extracellular bacterial and fungi (1, 2, 30–32).

ILCs originate from common lymphoid progenitors (CLPs), which subsequently differentiate into two different lineages: the common helper-like innate lymphocyte progenitors (CHILPs) and the conventional natural killer cell progenitors (cNKps) (Figure 2). However, CHILPs are a heterogeneous population consisting of innate lymphoid cell precursors (ILCPs) and lymphoid tissue-inducer precursors (LTiPs) (33, 34). CHILPs are defined as Lin⁻IL-7R⁺Flt-3⁻α4β7⁺CD25⁻ Id2^highPLZF⁺ cells and can give rise to ILC1, ILC2, ILC3, and LTi cells but not cNK cells (30, 33, 35). ILCPs are designated as Lin⁻CD127⁺α4β7⁺PLZF⁺ cells and can produce all ILC lineages (33). LTiPs are the precursors of LTi cells and are defined as Lin⁻CD127⁺α4β7⁺c-Kit⁺ RORγt⁺PLZF⁻ cells (33). cNKps can generate cNK cells and are unable to give rise to ILC2 and ILC3 cells. The development of cNK cells requires inhibitor of DNA binding 2 (Id2) (36–38), nuclear factor interleukin 3 (NFIL3) (39–42), thymocyte selection-associated high-mobility group box protein (TOX) (43, 44) and Eomesodermin (Eomes) (45, 46). However, the functional maturation and bone marrow egress of these cells requires T-bet (45–48). NFIL3 is involved in the development of bone marrow-derived NK cells from CLPs under homeostatic conditions and is necessary for the formation of splenic and thymic NK cells (39–42). Unlike cNK cells, ILC1 cells arise from Id2⁺PLZF⁺CHILP progenitor cells (49). Interestingly, the development of ILC2 cells requires Id2 (36, 37), GATA-binding protein 3 (GATA-3) (50–52), RORα (53), transcription factor 1 (TCF-1) (54–56), BCL11B (57, 58), and Notch (59, 60). GATA-3 is crucial for the secretion of effector cytokines, such as IL-5 and IL-13, by mature ILC2 cells (50–52, 61). In addition, Gfi1 can promote the development of ILC2 cells and control their responsiveness during infection by Nippostrongylus brasiliensis and protect against allergen-induced lung inflammation (62). Runx3 is another key factor in the differentiation of ILC1 and ILC3 cells. It controls the survival of ILC1 cells and is necessary for the expression of RORγt and AHR in ILC3 cells (7, 63).

ILC3 cells differentiate from Lin⁻IL-7Rα⁺Flt3⁻γ4β7⁺ fetal liver progenitors and express Id2 and RORγt in mice (1, 37). The development of murine LTi cells and LTi-like ILC3 cells requires the expression of RORγt, the aryl hydrocarbon receptor (AHR), RUNX3 and Notch (1, 2, 37, 64). The AHR seems to be involved in the expansion of CCR6^−/lowILC3 cells (65–68). AHR^−/− mice exhibit a decrease in CCR6^−/lowILC3 cells without alteration in the CCR6⁺ILC3 population. Furthermore, T-bet controls the fate and function of CCR6⁻RORγt⁺ILCs. Postnatal CCR6⁻RORγt⁺ILCs upregulate T-bet, which is modulated by the commensal microbiota. Tbx21^−/− mice exhibit normal development of CCR6⁻RORγt⁺ cells, but they fail to differentiate into NKp46⁺RORγt⁺ ILCs, suggesting that T-bet is necessary for the differentiation of NKp46⁺RORγt⁺ ILCs in mice (8, 69). Additionally, the IL-1β/IL-1R/MyD88 pathway controls the production of IL-22 by NKp46⁺RORγt⁺ILCs in the small intestine (SI) of mice (70). In contrast to mice, both human Lin⁻CD34⁺CD45RA⁺CD117⁺IL-1R⁺RORγt⁺ cells and stage 2 IL-1R⁺ cells in secondary lymphoid tissues (SLT) can differentiate into nearly all ILC populations including NK cells (71). Collectively, these results demonstrate that the development of ILCs is not dependent on a single “master regulator” but on a complex network of transcription factors (TFs) (1, 15, 31). Interestingly, recent studies have focused on the plasticity of ILCs. For instance, ILC1 cells can be converted into NK cells after ectopic expression of Eomes (31, 48). IL-12 can endow ILC2 cells with ILC1 features by secreting IFN-γ (60, 72), whereas IL-12 and IL-23 can induce the transition of ILC3 cells into ILC1 cells (60, 73, 74). Furthermore, dermal NCR⁻ILC3 cells can be transformed into NCR⁺ ILC3 cells in the presence of IL-1β and IL-23 in vitro (42, 75–77).

NK cells are mainly located in the bone marrow, lymph nodes, spleen, lungs, and liver, whereas ILC1 cells mainly reside in the intestinal intraepithelia (IE) (2, 78, 79). ILC2 cells are located in the lungs and lamina propria of the small intestine (SI) and skin, whereas ILC3 cells are predominantly located in the lamina propria, Peyer's patches and lymphoid follicles of the small intestine (78, 79).

It is generally considered that fetal liver and bone marrow are the “factories” where ILC subsets are generated (1, 2). However, a report by Gasteiger et al. have indicated that the vast majority of ILCs in both lymphoid and non-mymphoid organs are long-lived tissue-resident under steady state (80). Another elegant study by Di Santo JP's lab has proposed a model of “ILC-poiesis” and provided a mechanism by which tissue ILCs could be replenished from blood ILCPs in response to steady-state losses and under the circumstance of infection and inflammation (81–83).

Recently, increasing evidence has indicated that ILC1 and ILC3 cells can migrate into SLTs, depending on integrins and chemo-attractant receptors, whereas the migration of ILC2 cells from hematopoietic sites to target tissues is independent of the aforementioned receptors.

It has been indicated that the migration of NK cells to LNs via high endothelial cells (HEVs) might be mediated by CCR7 or CXCR3. The migration of ILC1 and ILC3 cells to SLTs occurs in a CCR7-dependent manner (84, 85). ILC2 cells, located in the bone marrow, spleen as well as mesenteric lymph nodes, constitutively express CCR9 and α4β7, rather than the RA-dependent homing receptor (79, 84). The migration of LTi-ILC3 cells to lymphoid follicles and the spleen marginal zone is regulated by the CXCL13-CXCR5 axis (86). Notably, trafficking receptor switches play a crucial role in the migration of ILCs. For instance, activation of spleen ILC3 cells induces upregulation of CCR9 and α4β7 with concomitant downregulation of CCR7 in the presence of IL-7 and all-trans retinoic acid (RA) and prompts the migration of these cells to the intestine (84, 87, 88).

Allogeneic hematopoietic stem cell transplantation (Allo-HSCT) is the most powerful therapy for hematologic malignancies and a majority of non-malignant hematological diseases. One of the major barriers to the efficacy of allo-HSCT is the occurrence of GVHD. Radiotherapy/chemotherapy induction regimens damage epithelia, especially the intestinal mucosa, in recipients, followed by the translocation of commensal microbiotas from the GI tract into the peripheral blood. Subsequent activation of adaptive immunity promotes the occurrence of aGVHD (89–94).

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.