Innate Lymphoid Cells Overview

Innate lymphoid cells (ILCs) are a group of innate effectors with transcriptional, functional, and phenotypic similarities to various T helper (Th) subsets. Like Th subsets, ILCs are found at mucosal surfaces and play important roles in immune response and protective immunity, and their deregulation can lead to pathological roles in allergic and autoimmune diseases. However, unlike Th cells that are dependent upon a cognate antigen for proliferation, ILCs constitutively express specific fate-determining transcription factors and do not respond in an antigen-specific manner.

ILCs include lineage marker negative (lin-) ILCs, natural killer (NK) cells, and lymphoid tissue-inducer (LTi) cells. Three distinct groups of ILCs have been classified based upon their immune response of Type 1, 2, and 3. Group 1 ILCs consists of IFN-γ–producing ILC1s or NK cells. Group 2 ILCs contain IL-5 and IL-13 , producing ILC2s, while Group 3 is comprised of ILC3s that are either IL-22-producing natural cytotoxicity receptor (NCR) positive, IL-17 producing NCR negative, or lymphotoxin-expressing Lymphoid Tissue-inducer (LTi) cells.

All ILCs are developmentally dependent on the transcription factor inhibitor of DNA-binding 2 (Id2). Group 1 ILCs include ILC1, which are similar to Th1 and are regulated by T-bet. Thus far, ILC1s are thought to be ILC3s that have lost RORγ(t) expression in response to a cytokine environment of IL-2, IL-12, and IL-18. NK cells are also considered a part of group 1 ILC and express transcription factor E4BP4 (NFIL3) upstream of Id2. Additionally, T-bet and Eomes direct their fate and function. Similar to Th2 cells, group 2 ILC2s rely on RORα and GATA3 for development. Finally, group 3 ILCs, which include natural cytotoxicity receptor NCR-positive IL-22–producing, NCR-negative IL-17–producing, and LTi cells, require RORγ(t) and aryl hydrocarbon receptor (AHR) for development similar to that of Th17 and Th22 cells.