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General educational overview for researchers and lab staff. It describes cell biology concepts only and is not medical advice.
Short answer
Innate lymphoid cells (ILCs) are lymphocytes that do not express the diversified antigen receptors found on T cells and B cells. They are mostly tissue-resident, sit at barrier surfaces such as the gut and lung, and are grouped into three types, ILC1, ILC2 and ILC3, by the cytokines they make and the transcription factors that drive them (Vivier et al., Cell 2018).
Definition and scope
ILCs are described as a family of lymphocytes that are the innate counterparts of T cells. Because they lack antigen-specific receptors, they sense tissue changes through cytokine receptors and through receptors for nutrient components, microbial products, lipid mediators and neuronal transmitters. They are primarily tissue resident, abundant at mucosal surfaces of the intestine and lung, and extremely rare in peripheral blood (Front Immunol 2019, PMC6515929).
The 2018 Cell review by Vivier and colleagues, written ten years after the cells were recognised as a distinct family, describes their roles at mucosal barriers in responses to commensals and pathogens, in potentiating adaptive immunity and in regulating tissue inflammation. It also notes roles beyond classical immunology, including metabolic homeostasis, tissue remodelling and dialogue with the nervous system, and it aims to refine ILC nomenclature in light of transcriptional networks and plasticity driven by the tissue microenvironment.
For the wider field these cells sit in, see what immunology covers.
The three ILC groups compared
The groups parallel T helper programmes: ILC1, ILC2 and ILC3 are defined by cytokines and transcription factors typically associated with Th1, Th2 and Th17 responses (Nat Rev Immunol 2015, PMID 26065585). The table below is limited to features stated in the 2019 Frontiers in Immunology review (PMC6515929).
| Group | Triggering signals | Signature effector cytokines | Key transcription factors | Human markers named in the review |
|---|---|---|---|---|
| ILC1 | IL-12, IL-15, IL-18 | IFN-γ | Mouse: Hobit and T-bet | Not tabulated here |
| ILC2 | TSLP, IL-25, IL-33 | IL-5, IL-9, IL-13, amphiregulin | Mouse: GATA3, RORα, TCF-1 | CRTH2, KLRG1, ST2, CD25 |
| ILC3 | Not tabulated here | IL-22, IL-17; also GM-CSF, TNF-α and (human) IL-26 | RORγt and AHR | NKp44, CD127, c-Kit, CCR6 |
Two related cell types are generally included in the family because they overlap with ILC1s and ILC3s: natural killer (NK) cells overlap with ILC1s, and lymphoid tissue inducer (LTi) cells overlap with ILC3s. In mice, NK cells need T-bet and Eomes, whereas ILC1s need Hobit and T-bet. LTi cells depend on RORγt and, in the embryo, drive lymph node and Peyer’s patch development through lymphotoxin.
ILC2 subsets
The same review distinguishes natural ILC2s (responsive to IL-33; Thy1 high, ST2 high, low KLRG1) from inflammatory ILC2s (responsive to IL-25; KLRG1 high, almost no ST2), and also describes IL-10-producing ILC2s. IL-13 from ILC2s is linked to helminth expulsion and tissue repair.
Where it matters in the lab
Mouse and human markers do not transfer one to one
- Mouse ILC2s are CD44+ CD161-, whereas human ILC2s are CD161+ CD44- (PMC6515929). A gating scheme copied from one species cannot be assumed to work in the other.
- The mouse transcription-factor split between ILC1 and NK cells does not hold cleanly in humans: human intraepithelial ILC1s express Eomes, while human hepatic NK cells do not.
- For cytometry panel design in general, see spectral flow cytometry and flow cytometry dyes.
Tissue choice shapes what you can find
- Because ILCs are extremely rare in peripheral blood, tissue sampling matters when the question concerns them (PMC6515929).
- Composition differs by site and age: ILC3s are the most abundant ILC subset in fetal and adult human intestine; in fetal gut ILC2 outnumber ILC1, while in adult gut ILC1 dominate over ILC2, and the distal ileum and colon are chiefly ILC3.
Host strain affects how ILC function is studied
Hepworth and colleagues (Nature 2013, PMID 23698371) note that experimental studies of ILC function have predominantly used mice lacking adaptive immune cells, because in lymphocyte-sufficient hosts ILCs are outnumbered by CD4+ T cells with similar cytokine profiles. Readers choosing models can compare NSG mice, and note the housing-status context in specific-pathogen-free mice.
Common misunderstandings
- “ILCs are just NK cells.” NK cells are generally included in the ILC family and overlap with ILC1s, but ILC2s and ILC3s have distinct cytokines, signals and transcription factors.
- “No antigen receptor means they ignore the environment.” ILCs lack diversified antigen receptors but read tissue signals through cytokine, nutrient, microbial, lipid and neuronal receptors.
- “The classification is settled.” Vivier et al. (2018) set out to refine the nomenclature because transcriptional networks and tissue-driven plasticity complicate categorisation.
- “ILC2s are the same as Th2 cells.” ILC2s are described as the innate counterpart of Th2 cells, not the same cell; the cytokine overlap is why separating them experimentally needs care.
FAQ
What are innate lymphoid cells?
Lymphocytes without diversified T- or B-cell-type antigen receptors, mostly resident in tissues, that respond to cytokines and other tissue signals.
How many types of ILC are there?
Three groups, ILC1, ILC2 and ILC3, with NK cells and LTi cells generally included in the family because of their overlap with ILC1s and ILC3s.
Where are ILCs found?
Mainly in tissues, and abundantly at mucosal surfaces of the intestine and lung. They are extremely rare in peripheral blood.
Sources
- Vivier E, et al. Innate Lymphoid Cells: 10 Years On. Cell 174(5):1054-1066 (2018). DOI 10.1016/j.cell.2018.07.017, PMID 30142344. Read via PubMed, 2026-11-08.
- Innate Lymphoid Cells in Mucosal Immunity. Front Immunol (2019), PMC6515929. Read via PMC, 2026-11-08.
- Review on transcriptional regulation of ILC fate. Nat Rev Immunol (2015), PMID 26065585. Abstract read via PubMed, 2026-11-08.
- Hepworth MR, et al. Nature (2013), PMID 23698371. Abstract read via PubMed, 2026-11-08.
