Robinette, M. L. & Colonna, M. Immune modules shared by innate lymphoid cells and T cells. J. Allergy Clin. Immunol. 138, 1243–1251 (2016).
Ding, Y. et al. Distinct developmental pathways generate functionally distinct populations of natural killer cells. Nat. Immunol. 25, 1183–1192 (2024). This study identified the earliest known NK-biased progenitors, termed ENKPs. The authors showed that NK cells arise by at least two developmental pathways, with another pathway of NK development mediated by ILCPs, and established that these NK cell subsets are functionally distinct.
Sun, J. C. & Lanier, L. L. NK cell development, homeostasis and function: parallels with CD8+ T cells. Nat. Rev. Immunol. 11, 645–657 (2011).
Vivier, E., van de Pavert, S. A., Cooper, M. D. & Belz, G. T. The evolution of innate lymphoid cells. Nat. Immunol. 17, 790–794 (2016).
Hirano, M. et al. Evolutionary implications of a third lymphocyte lineage in lampreys. Nature 501, 435–438 (2013).
Fugmann, S. D. The origins of the Rag genes–from transposition to V(D)J recombination. Semin. Immunol. 22, 10–16 (2010).
Eberl, G., Colonna, M., Di Santo, J. P. & McKenzie, A. N. Innate lymphoid cells: a new paradigm in immunology. Science 348, aaa6566 (2015).
Ebbo, M., Crinier, A., Vely, F. & Vivier, E. Innate lymphoid cells: major players in inflammatory diseases. Nat. Rev. Immunol. 17, 665–678 (2017).
Vivier, E. et al. Innate lymphoid cells: 10 years on. Cell 174, 1054–1066 (2018).
Artis, D. & Spits, H. The biology of innate lymphoid cells. Nature 517, 293–301 (2015).
Vely, F. et al. Evidence of innate lymphoid cell redundancy in humans. Nat. Immunol. 17, 1291–1299 (2016).
Sonnenberg, G. F., Monticelli, L. A., Elloso, M. M., Fouser, L. A. & Artis, D. CD4+ lymphoid tissue-inducer cells promote innate immunity in the gut. Immunity 34, 122–134 (2011).
Hepworth, M. R. et al. Immune tolerance. Group 3 innate lymphoid cells mediate intestinal selection of commensal bacteria-specific CD4+ T cells. Science 348, 1031–1035 (2015).
Sonnenberg, G. F. & Hepworth, M. R. Functional interactions between innate lymphoid cells and adaptive immunity. Nat. Rev. Immunol. 19, 599–613 (2019).
Nagasawa, M., Spits, H. & Ros, X. R. Innate lymphoid cells (ILCs): cytokine hubs regulating immunity and tissue homeostasis. Cold Spring Harb. Perspect. Biol. 10, a030304 (2018).
Yano, H. & Artis, D. Neuronal regulation of innate lymphoid cell responses. Curr. Opin. Immunol. 76, 102205 (2022).
Ryu, S., Lim, M., Kim, J. & Kim, H. Y. Versatile roles of innate lymphoid cells at the mucosal barrier: from homeostasis to pathological inflammation. Exp. Mol. Med. 55, 1845–1857 (2023).
Xiong, L., Nutt, S. L. & Seillet, C. Innate lymphoid cells: more than just immune cells. Front. Immunol. 13, 1033904 (2022).
Gasteiger, G., Fan, X., Dikiy, S., Lee, S. Y. & Rudensky, A. Y. Tissue residency of innate lymphoid cells in lymphoid and nonlymphoid organs. Science 350, 981–985 (2015).
Mackley, E. C. et al. CCR7-dependent trafficking of RORγ+ ILCs creates a unique microenvironment within mucosal draining lymph nodes. Nat. Commun. 6, 5862 (2015).
Das, A. et al. Transcription factor Tox2 is required for metabolic adaptation and tissue residency of ILC3 in the gut. Immunity 57, 1019–1036 (2024).
Ricardo-Gonzalez, R. R. et al. Tissue signals imprint ILC2 identity with anticipatory function. Nat. Immunol. 19, 1093–1099 (2018).
Martinez-Gonzalez, I. et al. Allergen-experienced group 2 innate lymphoid cells acquire memory-like properties and enhance allergic lung inflammation. Immunity 45, 198–208 (2016).
Serafini, N. et al. Trained ILC3 responses promote intestinal defense. Science 375, 859–863 (2022).
Trabanelli, S. et al. c-Maf enforces cytokine production and promotes memory-like responses in mouse and human type 2 innate lymphoid cells. EMBO J. 41, e109300 (2022).
Verma, M. et al. The molecular and epigenetic mechanisms of innate lymphoid cell (ILC) memory and its relevance for asthma. J. Exp. Med. 218, e20201354 (2021).
Sun, J. C., Beilke, J. N. & Lanier, L. L. Adaptive immune features of natural killer cells. Nature 457, 557–561 (2009).
Zook, E. C. & Kee, B. L. Development of innate lymphoid cells. Nat. Immunol. 17, 775–782 (2016).
Klose, C. S. N. et al. Differentiation of type 1 ILCs from a common progenitor to all helper-like innate lymphoid cell lineages. Cell 157, 340–356 (2014). This study identified Id2-expressing CHILPs, which predominantly generated helper ILCs and only a small fraction of NK cells.
Halim, T. Y., Krauss, R. H., Sun, A. C. & Takei, F. Lung natural helper cells are a critical source of Th2 cell-type cytokines in protease allergen-induced airway inflammation. Immunity 36, 451–463 (2012).
Hoyler, T. et al. The transcription factor GATA-3 controls cell fate and maintenance of type 2 innate lymphoid cells. Immunity 37, 634–648 (2012).
Moro, K. et al. Innate production of TH2 cytokines by adipose tissue-associated c-Kit+Sca-1+ lymphoid cells. Nature 463, 540–544 (2010).
Neill, D. R. et al. Nuocytes represent a new innate effector leukocyte that mediates type-2 immunity. Nature 464, 1367–1370 (2010).
Price, A. E. et al. Systemically dispersed innate IL-13-expressing cells in type 2 immunity. Proc. Natl Acad. Sci. USA 107, 11489–11494 (2010).
Spits, H. & Cupedo, T. Innate lymphoid cells: emerging insights in development, lineage relationships, and function. Annu. Rev. Immunol. 30, 647–675 (2012).
Spits, H. et al. Innate lymphoid cells–a proposal for uniform nomenclature. Nat. Rev. Immunol. 13, 145–149 (2013).
Eberl, G. et al. An essential function for the nuclear receptor RORγt in the generation of fetal lymphoid tissue inducer cells. Nat. Immunol. 5, 64–73 (2003).
Weizman, O. E. et al. ILC1 confer early host protection at initial sites of viral infection. Cell 171, 795–808 (2017).
Abt, M. C. et al. Innate immune defenses mediated by two ILC subsets are critical for protection against acute Clostridium difficile infection. Cell Host Microbe 18, 27–37 (2015).
Walker, J. A. & McKenzie, A. N. Development and function of group 2 innate lymphoid cells. Curr. Opin. Immunol. 25, 148–155 (2013).
Wallrapp, A., Riesenfeld, S. J., Burkett, P. R. & Kuchroo, V. K. Type 2 innate lymphoid cells in the induction and resolution of tissue inflammation. Immunol. Rev. 286, 53–73 (2018).
Domingues, R. G. & Hepworth, M. R. Immunoregulatory sensory circuits in group 3 innate lymphoid cell (ILC3) function and tissue homeostasis. Front. Immunol. 11, 116 (2020).
Longman, R. S. et al. CX3CR1+ mononuclear phagocytes support colitis-associated innate lymphoid cell production of IL-22. J. Exp. Med. 211, 1571–1583 (2014).
Song, C. et al. Unique and redundant functions of NKp46+ ILC3s in models of intestinal inflammation. J. Exp. Med. 212, 1869–1882 (2015).
Pearson, C. et al. ILC3 GM-CSF production and mobilisation orchestrate acute intestinal inflammation. eLife 5, e10066 (2016).
Gordon, S. M. et al. The transcription factors T-bet and Eomes control key checkpoints of natural killer cell maturation. Immunity 36, 55–67 (2012).
Kupz, A. et al. Contribution of Thy1+ NK cells to protective IFN-γ production during Salmonella typhimurium infections. Proc. Natl Acad. Sci. USA 110, 2252–2257 (2013).
Chiossone, L. & Vivier, E. Bringing natural killer cells to the clinic. J. Exp. Med. 219, e20220830 (2022).
van de Pavert, S. A. Lymphoid tissue inducer (LTi) cell ontogeny and functioning in embryo and adult. Biomed J 44, 123–132 (2021).
Colonna, M. Interleukin-22-producing natural killer cells and lymphoid tissue inducer-like cells in mucosal immunity. Immunity 31, 15–23 (2009).
Cupedo, T. et al. Human fetal lymphoid tissue-inducer cells are interleukin 17-producing precursors to RORC+ CD127+ natural killer-like cells. Nat. Immunol. 10, 66–74 (2009).
Sun, Z. et al. Requirement for RORγ in thymocyte survival and lymphoid organ development. Science 288, 2369–2373 (2000).
Bouskra, D. et al. Lymphoid tissue genesis induced by commensals through NOD1 regulates intestinal homeostasis. Nature 456, 507–510 (2008).
Constantinides, M. G., McDonald, B. D., Verhoef, P. A. & Bendelac, A. A committed precursor to innate lymphoid cells. Nature 508, 397–401 (2014). This study used lineage tracing to show that PLZF-expressing committed ILCPs give rise to all ILCs. The work indicated that most NK cells and LTi cells have distinct developmental pathways from ILC1s, ILC2s and ILC3s.
Ren, G. et al. Decreased GATA3 levels cause changed mouse cutaneous innate lymphoid cell fate, facilitating hair follicle recycling. Dev. Cell 59, 1809–1823 (2024).
Sawa, S. et al. Lineage relationship analysis of RORγt+ innate lymphoid cells. Science 330, 665–669 (2010).
Krabbendam, L., Bernink, J. H. & Spits, H. Innate lymphoid cells: from helper to killer. Curr. Opin. Immunol. 68, 28–33 (2021).
Bal, S. M., Golebski, K. & Spits, H. Plasticity of innate lymphoid cell subsets. Nat. Rev. Immunol. 20, 552–565 (2020).
Colonna, M. Innate lymphoid cells: diversity, plasticity, and unique functions in immunity. Immunity 48, 1104–1117 (2018).
Bernink, J. H. et al. Interleukin-12 and -23 control plasticity of CD127+ group 1 and group 3 innate lymphoid cells in the intestinal lamina propria. Immunity 43, 146–160 (2015).
Cella, M. et al. Subsets of ILC3-ILC1-like cells generate a diversity spectrum of innate lymphoid cells in human mucosal tissues. Nat. Immunol. 20, 980–991 (2019).
Akagbosu, B. et al. Novel antigen-presenting cell imparts Treg-dependent tolerance to gut microbiota. Nature 610, 752–760 (2022).
Kedmi, R. et al. A RORγt+ cell instructs gut microbiota-specific Treg cell differentiation. Nature 610, 737–743 (2022).
Lyu, M. et al. ILC3s select microbiota-specific regulatory T cells to establish tolerance in the gut. Nature 610, 744–751 (2022).
Rodrigues, P. F. et al. Rorγt-positive dendritic cells are required for the induction of peripheral regulatory T cells in response to oral antigens. Cell 188, 2720–2737 (2025).
Wang, J. et al. Single-cell multiomics defines tolerogenic extrathymic Aire-expressing populations with unique homology to thymic epithelium. Sci. Immunol. 6, eabl5053 (2021).
Fu, L. et al. PRDM16-dependent antigen-presenting cells induce tolerance to gut antigens. Nature 642, 756–765 (2025).
Narasimhan, H. et al. RORγt-expressing dendritic cells are functionally versatile and evolutionarily conserved antigen-presenting cells. Proc. Natl Acad. Sci. USA 122, e2417308122 (2025).
Sun, I. H. et al. RORγt eTACs mediate oral tolerance and Treg induction. J. Exp. Med. 222, e20250573 (2025).
Hepworth, M. R. et al. Innate lymphoid cells regulate CD4+ T-cell responses to intestinal commensal bacteria. Nature 498, 113–117 (2013).
Hoelting, T. L. B., Park, T. & Brown, C. C. Antigen-presenting cells as arbiters of mucosal tolerance and immunity. Nat. Immunol. 26, 1890–−1902 (2025).
Klose, C. S. et al. A T-bet gradient controls the fate and function of CCR6-RORγt+ innate lymphoid cells. Nature 494, 261–265 (2013).
Vonarbourg, C. et al. Regulated expression of nuclear receptor RORγt confers distinct functional fates to NK cell receptor-expressing RORγt+ innate lymphocytes. Immunity 33, 736–751 (2010).
Wang, X. et al. Innate lymphoid cells originate from fetal liver-derived tissue-resident progenitors. Sci. Immunol. 10, eadu7962 (2025). This study showed that extramedullary and intramedullary ILCs in mice have separate developmental origins during ontogeny. The local microenvironment instructs ILCP fate, directing them toward bipotent ILC1P/ILC3P in liver and intestine, and ILC2P in lung.
Yang, Q. & Bhandoola, A. The development of adult innate lymphoid cells. Curr. Opin. Immunol. 39, 114–120 (2016).
Kondo, M., Weissman, I. L. & Akashi, K. Identification of clonogenic common lymphoid progenitors in mouse bone marrow. Cell 91, 661–672 (1997).
Inlay, M. A. et al. Ly6d marks the earliest stage of B-cell specification and identifies the branchpoint between B-cell and T-cell development. Genes Dev. 23, 2376–2381 (2009).
Adolfsson, J. et al. Identification of Flt3+ lympho-myeloid stem cells lacking erythro-megakaryocytic potential a revised road map for adult blood lineage commitment. Cell 121, 295–306 (2005).
Welner, R. S. et al. Lymphoid precursors are directed to produce dendritic cells as a result of TLR9 ligation during herpes infection. Blood 112, 3753–3761 (2008).
Bell, J. J. & Bhandoola, A. The earliest thymic progenitors for T cells possess myeloid lineage potential. Nature 452, 764–767 (2008).
Das, A., Harly, C., Ding, Y. & Bhandoola, A. ILC differentiation from progenitors in the bone marrow. Adv. Exp. Med. Biol. 1365, 7–24 (2022).
Ghaedi, M. et al. Common-lymphoid-progenitor-independent pathways of innate and T lymphocyte development. Cell Rep. 15, 471–480 (2016).
Adolfsson, J. et al. Upregulation of Flt3 expression within the bone marrow Lin−Sca1+c-kit+ stem cell compartment is accompanied by loss of self-renewal capacity. Immunity 15, 659–669 (2001).
Harly, C., Cam, M., Kaye, J. & Bhandoola, A. Development and differentiation of early innate lymphoid progenitors. J. Exp. Med. 215, 249–262 (2018). The authors established EILPs as developmental intermediates between ALPs and ILCPs, and characterized key transcriptional requirements at successive stages of ILC development.
Diefenbach, A., Colonna, M. & Koyasu, S. Development, differentiation, and diversity of innate lymphoid cells. Immunity 41, 354–365 (2014).
Tufa, D. M. et al. Human innate lymphoid cell precursors express CD48 that modulates ILC differentiation through 2B4 signaling. Sci. Immunol. 5, eaay421 (2020).
Yu, X. et al. The basic leucine zipper transcription factor NFIL3 directs the development of a common innate lymphoid cell precursor. eLife 3, e04406 (2014). This work, together with Seillet et al. (2014) and Xu et al. (2015), showed that NFIL3 is essential for generating nearly all ILCs. The authors characterized a CXCR6+ αLP population that differentiated into ILCs but not T cells or B cells.
Possot, C. et al. Notch signaling is necessary for adult, but not fetal, development of RORγt+ innate lymphoid cells. Nat. Immunol. 12, 949–958 (2011).
Yoshida, H. et al. Expression of α4β7 integrin defines a distinct pathway of lymphoid progenitors committed to T cells, fetal intestinal lymphotoxin producer, NK, and dendritic cells. J. Immunol. 167, 2511–2521 (2001).
Yu, Y. et al. Single-cell RNA-seq identifies a PD-1hi ILC progenitor and defines its development pathway. Nature 539, 102–106 (2016).
Xu, W. et al. An Id2RFP-reporter mouse redefines innate lymphoid cell precursor potentials. Immunity 50, 1054–1068 (2019).
Yang, Q. et al. TCF-1 upregulation identifies early innate lymphoid progenitors in the bone marrow. Nat. Immunol. 16, 1044–1050 (2015). This work identified a population of EILPs marked by high TCF-1 expression that efficiently differentiated into NK cells, ILC1s, ILC2s and ILC3s.
Kasal, D. N. & Bendelac, A. Multi-transcription factor reporter mice delineate early precursors to the ILC and LTi lineages. J. Exp. Med. 218, e20200487 (2021). This study identified the earliest specified precursor for LTi cells, termed Rorc+ αLP, which expressed RORγt but lacked TCF-1.
Harly, C. et al. The transcription factor TCF-1 enforces commitment to the innate lymphoid cell lineage. Nat. Immunol. 20, 1150–1160 (2019).
Leger, J. et al. The transcription factor NFIL3 drives innate lymphoid cell specification from lymphoid progenitors. Immunity 58, 2685–2703 (2025). This study showed that forced expression of NFIL3 in ALPs led to upregulated expression of many ILC transcription factors including TOX, TCF-1 and PLZF, and differentiation of ILCs in vitro. Genome-wide NFIL3 binding studies indicated NFIL3 provided direct regulatory inputs to many ILC genes.
Cortez, V. S., Fuchs, A., Cella, M., Gilfillan, S. & Colonna, M. Cutting edge: salivary gland NK cells develop independently of Nfil3 in steady-state. J. Immunol. 192, 4487–4491 (2014).
Geiger, T. L. et al. Nfil3 is crucial for development of innate lymphoid cells and host protection against intestinal pathogens. J. Exp. Med. 211, 1723–1731 (2014).
Male, V. et al. The transcription factor E4bp4/Nfil3 controls commitment to the NK lineage and directly regulates Eomes and Id2 expression. J. Exp. Med. 211, 635–642 (2014).
Seillet, C. et al. Differential requirement for Nfil3 during NK cell development. J. Immunol. 192, 2667–2676 (2014).
Seillet, C. et al. Nfil3 is required for the development of all innate lymphoid cell subsets. J. Exp. Med. 211, 1733–1740 (2014).
Xu, W. et al. NFIL3 orchestrates the emergence of common helper innate lymphoid cell precursors. Cell Rep. 10, 2043–2054 (2015).
Gascoyne, D. M. et al. The basic leucine zipper transcription factor E4BP4 is essential for natural killer cell development. Nat. Immunol. 10, 1118–1124 (2009).
Dadi, S. et al. Cancer immunosurveillance by tissue-resident innate lymphoid cells and innate-like T cells. Cell 164, 365–377 (2016).
Doisne, J. M. et al. Composition, development, and function of uterine innate lymphoid cells. J. Immunol. 195, 3937–3945 (2015).
Sojka, D. K. et al. Tissue-resident natural killer (NK) cells are cell lineages distinct from thymic and conventional splenic NK cells. eLife 3, e01659 (2014).
Seehus, C. R. et al. The development of innate lymphoid cells requires TOX-dependent generation of a common innate lymphoid cell progenitor. Nat. Immunol. 16, 599–608 (2015). This study showed that the transcription factor TOX is essential for development of all known ILC subsets and early ILC progenitors, but not ILC3 in the gut.
Erick, T. K., Anderson, C. K., Reilly, E. C., Wands, J. R. & Brossay, L. NFIL3 expression distinguishes tissue-resident NK cells and conventional NK-like cells in the mouse submandibular glands. J. Immunol. 197, 2485–2491 (2016).
Schneider, C. et al. Tissue-resident group 2 innate lymphoid cells differentiate by layered ontogeny and in situ perinatal priming. Immunity 50, 1425–1438 (2019).
van de Pavert, S. A. Layered origins of lymphoid tissue inducer cells. Immunol. Rev. 315, 71–78 (2023).
Zeis, P. et al. In situ maturation and tissue adaptation of type 2 innate lymphoid cell progenitors. Immunity 53, 775–792 (2020).
Das, A., Harly, C., Yang, Q. & Bhandoola, A. Lineage specification in innate lymphocytes. Cytokine Growth Factor Rev. 42, 20–26 (2018).
Halim, T. Y. et al. Retinoic-acid-receptor-related orphan nuclear receptor alpha is required for natural helper cell development and allergic inflammation. Immunity 37, 463–474 (2012).
Walker, J. A. et al. Polychromic reporter mice reveal unappreciated innate lymphoid cell progenitor heterogeneity and elusive ILC3 progenitors in bone marrow. Immunity 51, 104–118 (2019).
Juelke, K. & Romagnani, C. Differentiation of human innate lymphoid cells (ILCs). Curr. Opin. Immunol. 38, 75–85 (2016).
Su, X., Deng, Z., Lan, Y., Liu, B. & Liu, C. Helper ILCs in the human hematopoietic system. Trends Immunol. 46, 244–257 (2025).
Hernández, D. C. et al. An in vitro platform supports generation of human innate lymphoid cells from CD34+ hematopoietic progenitors that recapitulate ex vivo identity. Immunity 54, 2417–2432 (2021).
Montaldo, E. et al. Human RORγt+CD34+ cells are lineage-specified progenitors of group 3 RORγt+ innate lymphoid cells. Immunity 41, 988–1000 (2014).
Goh, W. & Huntington, N. D. Regulation of murine natural killer cell development. Front. Immunol. 8, 130 (2017).
Fathman, J. W. et al. Identification of the earliest natural killer cell-committed progenitor in murine bone marrow. Blood 118, 5439–5447 (2011).
Constantinides, M. G. et al. PLZF expression maps the early stages of ILC1 lineage development. Proc. Natl Acad. Sci. USA 112, 5123–5128 (2015).
Flommersfeld, S. et al. Fate mapping of single NK cells identifies a type 1 innate lymphoid-like lineage that bridges innate and adaptive recognition of viral infection. Immunity 54, 2288–2304 (2021).
Sparano, C. et al. Autocrine TGF-β1 drives tissue-specific differentiation and function of resident NK cells. J. Exp. Med. 222, e20240930 (2025).
Rebuffet, L. et al. High-dimensional single-cell analysis of human natural killer cell heterogeneity. Nat. Immunol. 25, 1474–1488 (2024).
Du, X. et al. Human-Induced CD49a+ NK cells promote fetal growth. Front. Immunol. 13, 821542 (2022).
Bottcher, J. P. et al. NK cells stimulate recruitment of cDC1 into the tumor microenvironment promoting cancer immune control. Cell 172, 1022–1037 (2018).
Morrison, T. A. et al. Selective requirement of glycosphingolipid synthesis for natural killer and cytotoxic T cells. Cell 188, 3497–3512.e16 (2025).
Li, J. H. et al. MEF2C regulates NK cell effector functions through control of lipid metabolism. Nat. Immunol. 25, 778–789 (2024).
Rodriguez-Rodriguez, N. et al. Identification of aceNKPs, a committed common progenitor population of the ILC1 and NK cell continuum. Proc. Natl Acad. Sci. USA 119, e2203454119 (2022).
Liang, Z. et al. Eomes expression identifies the early bone marrow precursor to classical NK cells. Nat. Immunol. 25, 1172–1182 (2024). This study identified and characterized an EOMES-expressing NK progenitor population that was heterogenous, and included committed NK progenitors but also some PLZF-expressing cells that generated both ILC1s and NK cells.
Chiossone, L. et al. Maturation of mouse NK cells is a 4-stage developmental program. Blood 113, 5488–5496 (2009).
Huntington, N. D. et al. NK cell maturation and peripheral homeostasis is associated with KLRG1 up-regulation. J. Immunol. 178, 4764–4770 (2007).
Boos, M. D., Yokota, Y., Eberl, G. & Kee, B. L. Mature natural killer cell and lymphoid tissue-inducing cell development requires Id2-mediated suppression of E protein activity. J. Exp. Med. 204, 1119–1130 (2007).
Cherrier, M., Sawa, S. & Eberl, G. Notch, Id2, and RORγt sequentially orchestrate the fetal development of lymphoid tissue inducer cells. J. Exp. Med. 209, 729–740 (2012).
Simic, M. et al. Distinct waves from the hemogenic endothelium give rise to layered lymphoid tissue inducer cell ontogeny. Cell Rep. 32, 108004 (2020). This study identified the origin of embryonic LTi cells as hematopoietic cells derived from the aorta–gonad–mesonephros region, rather than the yolk sac.
Ishizuka, I. E. et al. Single-cell analysis defines the divergence between the innate lymphoid cell lineage and lymphoid tissue-inducer cell lineage. Nat. Immunol. 17, 269–276 (2016).
Chea, S. et al. Single-cell gene expression analyses reveal heterogeneous responsiveness of fetal innate lymphoid progenitors to Notch signaling. Cell Rep. 14, 1500–1516 (2016).
Zhong, C. et al. Differential expression of the transcription factor GATA3 specifies lineage and functions of innate lymphoid cells. Immunity 52, 83–95 (2020).
Zheng, M. et al. Transcription factor TCF-1 regulates the functions, but not the development, of lymphoid tissue inducer subsets in different tissues. Cell Rep. 42, 112924 (2023).
Bando, J. K., Liang, H.-E. & Locksley, R. M. Identification and distribution of developing innate lymphoid cells in the fetal mouse intestine. Nat. Immunol. 16, 153–160 (2014).
Stehle, C. et al. T-bet and RORα control lymph node formation by regulating embryonic innate lymphoid cell differentiation. Nat. Immunol. 22, 1231–1244 (2021).
Bai, L. et al. Liver type 1 innate lymphoid cells develop locally via an interferon-γ-dependent loop. Science 371, eaba4177 (2021).
Ni, Y. et al. Human yolk sac-derived innate lymphoid-biased multipotent progenitors emerge prior to hematopoietic stem cell formation. Dev. Cell 59, 2626–2642 (2024).
Lim, A. I. & Di Santo, J. P. ILC-poiesis: ensuring tissue ILC differentiation at the right place and time. Eur. J. Immunol. 49, 11–18 (2019).
Clark, P. A. et al. Recipient tissue microenvironment determines developmental path of intestinal innate lymphoid progenitors. Nat. Commun. 15, 7809 (2024).
Lim, A. I. et al. Systemic human ILC precursors provide a substrate for tissue ILC differentiation. Cell 168, 1086–1100 (2017). This study identified ILCPs in human peripheral blood that gave rise to ILC1s, ILC2s and ILC3s. Distinct ILC populations in different tissues might be generated from colonizing multipotential ILC precursors responding to tissue-specific signals, which the authors termed ‘ILC-poiesis’.
Di Santo, J. P., Lim, A. I. & Yssel, H. ‘ILC-poiesis’: generating tissue ILCs from naive precursors. Oncotarget 8, 81729–81730 (2017).
Lefrançais, E. et al. The lung is a site of platelet biogenesis and a reservoir for haematopoietic progenitors. Nature 544, 105–109 (2017).
Ghaedi, M. et al. Single-cell analysis of RORα tracer mouse lung reveals ILC progenitors and effector ILC2 subsets. J. Exp. Med. 217, jem.20182293 (2020).
Oherle, K. et al. Insulin-like growth factor 1 supports a pulmonary niche that promotes type 3 innate lymphoid cell development in newborn lungs. Immunity 52, 275–294 (2020).
Huang, Q. et al. GFI1B specifies developmental potential of innate lymphoid cell progenitors in the lungs. Sci. Immunol. 9, eadj2654 (2024).
Koga, S. et al. Peripheral PDGFRα+gp38+ mesenchymal cells support the differentiation of fetal liver-derived ILC2. J. Exp. Med. 215, 1609–1626 (2018).
Spencer, S. P. et al. Adaptation of innate lymphoid cells to a micronutrient deficiency promotes type 2 barrier immunity. Science 343, 432–437 (2014).
Scoville, S. D., Freud, A. G. & Caligiuri, M. A. Cellular pathways in the development of human and murine innate lymphoid cells. Curr. Opin. Immunol. 56, 100–106 (2019).
Scoville, S. D. et al. A progenitor cell expressing transcription factor RORγt generates all human innate lymphoid cell subsets. Immunity 44, 1140–1150 (2016).
Chen, L. et al. CD56 expression marks human group 2 innate lymphoid cell divergence from a shared NK cell and group 3 innate lymphoid cell developmental pathway. Immunity 49, 464–476 (2018).
Liu, C. et al. Delineating spatiotemporal and hierarchical development of human fetal innate lymphoid cells. Cell Res. 31, 1106–1122 (2021).
Nagasawa, M. et al. KLRG1 and NKp46 discriminate subpopulations of human CD117+CRTH2− ILCs biased toward ILC2 or ILC3. J. Exp. Med. 216, 1762–1776 (2019).
De Obaldia, M. E. & Bhandoola, A. Transcriptional regulation of innate and adaptive lymphocyte lineages. Annu. Rev. Immunol. 33, 607–642 (2015).
Spinner, C. A. & Lazarevic, V. Transcriptional regulation of adaptive and innate lymphoid lineage specification. Immunol. Rev. 300, 65–81 (2021).
Cherrier, M., Ramachandran, G. & Golub, R. The interplay between innate lymphoid cells and T cells. Mucosal Immunol. 13, 732–742 (2020).
Ding, Y., Harly, C., Das, A. & Bhandoola, A. Early development of innate lymphoid cells. Methods Mol. Biol. 2580, 51–69 (2023).
Seillet, C. et al. Deciphering the innate lymphoid cell transcriptional program. Cell Rep 17, 436–447 (2016).
Serafini, N., Vosshenrich, C. A. & Di Santo, J. P. Transcriptional regulation of innate lymphoid cell fate. Nat. Rev. Immunol. 15, 415–428 (2015).
Yagi, R. et al. The transcription factor GATA3 is critical for the development of all IL-7Rα-expressing innate lymphoid cells. Immunity 40, 378–388 (2014).
Shih, H. Y. et al. Developmental acquisition of regulomes underlies innate lymphoid cell functionality. Cell 165, 1120–1133 (2016).
Shih, H. Y. et al. Transcriptional and epigenetic networks of helper T and innate lymphoid cells. Immunol. Rev. 261, 23–49 (2014).
Fang, D., Healy, A. & Zhu, J. Differential regulation of lineage-determining transcription factor expression in innate lymphoid cell and adaptive T helper cell subsets. Front. Immunol. 13, 1081153 (2022).
Germar, K. et al. T-cell factor 1 is a gatekeeper for T-cell specification in response to Notch signaling. Proc. Natl Acad. Sci. USA 108, 20060–20065 (2011).
Pai, S. Y. et al. Critical roles for transcription factor GATA-3 in thymocyte development. Immunity 19, 863–875 (2003).
Ren, G. et al. Transcription factors TCF-1 and GATA3 are key factors for the epigenetic priming of early innate lymphoid progenitors toward distinct cell fates. Immunity 55, 1402–1413 (2022).
Weber, B. N. et al. A critical role for TCF-1 in T-lineage specification and differentiation. Nature 476, 63–68 (2011).
Hosoya, T. et al. GATA-3 is required for early T lineage progenitor development. J. Exp. Med. 206, 2987–3000 (2009).
Kasal, D. N. et al. A Gata3 enhancer necessary for ILC2 development and function. Proc. Natl Acad. Sci. USA 118, e2106311118 (2021).
Ohmura, S. et al. Lineage-affiliated transcription factors bind the Gata3 Tce1 enhancer to mediate lineage-specific programs. J. Clin. Invest. 126, 865–878 (2016).
Goldman, N. et al. Intrinsically disordered domain of transcription factor TCF-1 is required for T cell developmental fidelity. Nat. Immunol. 24, 1698–1710 (2023).
Savage, A. K. et al. The transcription factor PLZF directs the effector program of the NKT cell lineage. Immunity 29, 391–403 (2008).
Taghon, T., Yui, M. A. & Rothenberg, E. V. Mast cell lineage diversion of T lineage precursors by the essential T cell transcription factor GATA-3. Nat. Immunol. 8, 845–855 (2007).
Aliahmad, P. et al. TOX provides a link between calcineurin activation and CD8 lineage commitment. J. Exp. Med. 199, 1089–1099 (2004).
Aliahmad, P., Kadavallore, A., de la Torre, B., Kappes, D. & Kaye, J. TOX is required for development of the CD4 T cell lineage gene program. J. Immunol. 187, 5931–5940 (2011).
Ikawa, T. et al. An essential developmental checkpoint for production of the T cell lineage. Science 329, 93–96 (2010).
Li, L., Leid, M. & Rothenberg, E. V. An early T cell lineage commitment checkpoint dependent on the transcription factor Bcl11b. Science 329, 89–93 (2010).
Li, P. et al. Reprogramming of T cells to natural killer-like cells upon Bcl11b deletion. Science 329, 85–89 (2010).
Califano, D. et al. Transcription factor Bcl11b controls identity and function of mature type 2 innate lymphoid cells. Immunity 43, 354–368 (2015).
Walker, J. A. et al. Bcl11b is essential for group 2 innate lymphoid cell development. J. Exp. Med. 212, 875–882 (2015).
Yu, Y. et al. The transcription factor Bcl11b is specifically expressed in group 2 innate lymphoid cells and is essential for their development. J. Exp. Med. 212, 865–874 (2015).
Hosokawa, H. et al. Cell type-specific actions of Bcl11b in early T-lineage and group 2 innate lymphoid cells. J. Exp. Med. 217, e20190972 (2020).
Miyazaki, M. et al. The E–Id protein axis specifies adaptive lymphoid cell identity and suppresses thymic innate lymphoid cell development. Immunity 46, 818–834 (2017).
Wang, H. C. et al. Downregulation of E protein activity augments an ILC2 differentiation program in the thymus. J. Immunol. 198, 3149–3156 (2017).
Nagasawa, M., Germar, K., Blom, B. & Spits, H. Human CD5+ innate lymphoid cells are functionally immature and their development from CD34+ progenitor cells is regulated by Id2. Front. Immunol. 8, 1047 (2017).
Monticelli, L. A. et al. Innate lymphoid cells promote lung-tissue homeostasis after infection with influenza virus. Nat. Immunol. 12, 1045–1054 (2011).
Satoh-Takayama, N. et al. IL-7 and IL-15 independently program the differentiation of intestinal CD3−NKp46+ cell subsets from Id2-dependent precursors. J. Exp. Med. 207, 273–280 (2010).
Yokota, Y. et al. Development of peripheral lymphoid organs and natural killer cells depends on the helix–loop–helix inhibitor Id2. Nature 397, 702–706 (1999).
Kamizono, S. et al. Nfil3/E4bp4 is required for the development and maturation of NK cells in vivo. J. Exp. Med. 206, 2977–2986 (2009).
Golub, R. The Notch signaling pathway involvement in innate lymphoid cell biology. Biomed. J. 44, 133–143 (2021).
Schmitt, T. M. & Zuniga-Pflucker, J. C. Induction of T cell development from hematopoietic progenitor cells by delta-like-1 in vitro. Immunity 17, 749–756 (2002).
Skene, P. J. & Henikoff, S. An efficient targeted nuclease strategy for high-resolution mapping of DNA binding sites. eLife 6, e21856 (2017).
Patey, E. & Bjorkstrom, N. K. Elusive early NK cell progenitor identified. Nat. Immunol. 25, 1126–1128 (2024).
Taniguchi, H., Toyoshima, T., Fukao, K. & Nakauchi, H. Presence of hematopoietic stem cells in the adult liver. Nat. Med. 2, 198–203 (1996).
Wang, X. Q. et al. Hematopoietic chimerism in liver transplantation patients and hematopoietic stem/progenitor cells in adult human liver. Hepatology 56, 1557–1566 (2012).
Freud, A. G. et al. A human CD34+ subset resides in lymph nodes and differentiates into CD56bright natural killer cells. Immunity 22, 295–304 (2005).
Renoux, V. M. et al. Identification of a human natural killer cell lineage-restricted progenitor in fetal and adult tissues. Immunity 43, 394–407 (2015).
Ferreira, A. C. F. et al. RORα is a critical checkpoint for T cell and ILC2 commitment in the embryonic thymus. Nat. Immunol. 22, 166–178 (2021).
Carlyle, J. R. et al. Identification of a novel developmental stage marking lineage commitment of progenitor thymocytes. J. Exp. Med. 186, 173–182 (1997).