Study of the interleukin-23 (IL-23)–IL-17 pathway has greatly changed our understanding of autoimmune inflammatory mechanisms. This Review highlights the many known and newly identified innate IL-17-producing cell populations found in the skin, gut, lungs and associated lymphoid organs.
We describe the cytokine and transcriptional regulation of innate IL-17-producing cells, with an emphasis on the crucial roles of IL-23 receptor signalling and retinoic acid receptor-related orphan receptor-γt (RORγt) in their development and/or function.
Innate IL-17 and IL-22 have physiological roles in immune surveillance, which include maintenance of mucosal barrier integrity, induction of antimicrobial protein production by epithelial cells and recruitment of inflammatory myeloid cells to the site of injury.
Current evidence suggests that early IL-17 and IL-22 secretion by innate cells shapes the balance of mucosal homeostasis and inflammation; we discuss the potential for autoimmunity if this system is dysregulated.
We provide insight into the future direction of research in this area and describe the potential implications for the development of new therapeutic agents.
The cytokine interleukin-17 (IL-17) has received considerable attention since the discovery of a distinct CD4+ T helper (TH) cell subset that produces it, known as the TH17 cell subset. Despite the fact that most of the recent literature describes IL-17 as a T cell-secreted cytokine, much of the IL-17 released during an inflammatory response is produced by innate immune cells. In this Review, we explore the many innate immune cell populations that are an early source of IL-17 in response to stress, injury or pathogens. These early sources have been shown to have a central role in the initiation of IL-17-dependent immune responses, even before the first CD4+T cell sees its cognate antigen and initiates the TH17 cell developmental programme.
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We thank M. McGeachy and K. Boniface for insightful discussion and R. Kastelein for critical reading of the manuscript.
The authors declare no competing financial interests.
- Recombination-activating gene
(RAG). Expressed by developing lymphocytes, mice that are deficient for either Rag1 or Rag2 fail to produce B or T cells owing to a developmental block in the gene rearrangement that is necessary for receptor expression.
- γδ T cell
A T cell that expresses a TCR consisting of a γ-chain and a δ-chain. These T cells are present in the intestinal epithelium as intraepithelial lymphocytes. γδ T cells are also present in the lungs, skin, liver and other tissue sites during inflammation. γδ T cells are thought to have an important role in innate immune responses, particularly in mucosal tissues.
- Invariant natural killer T (iNKT) cell
A T cell that expresses a particular variable gene segment, Vα14 (in mice) and Vα 24 (in humans), precisely rearranged to a particular Jα (joining) gene segment to yield T cell receptor α-chains with an invariant sequence. Typically, these cells co-express cell-surface markers that are encoded by the natural killer (NK) locus, and they are activated by recognition of CD1d, particularly when α-galactosylceramide is bound in the groove of CD1d.
- Common cytokine-receptor γ-chain
A chain common to type I cytokine receptors. It was first discovered as the γ-chain of the IL-2 receptor and was subsequently shown also to be present in the receptors for IL-4, IL-7, IL-9, IL-15 and IL-21. It is mutated in humans with X-linked severe combined immunodeficiency.
- Ischaemia–reperfusion injury
An injury in which the tissue first suffers from hypoxia as a result of severely decreased, or completely arrested, blood flow. Restoration of normal blood flow then triggers inflammation, which exacerbates the tissue damage.
- Tight junction
A belt-like region of adhesion between adjacent epithelial or endothelial cells that regulates paracellular flux. Tight junction proteins include the integral membrane proteins occludin and claudin, in association with cytoplasmic zonula occludens proteins.
- Blood–brain barrier
A physiological barrier between blood vessels and brain parenchyma. It is formed by specialized tight junctions between endothelial cells of the blood vessel wall, which is surrounded by a basement membrane and an additional membrane formed from astrocyte feet and microglial cells, known as the glial limitin.
- IL-23ReGFP and RORγteGFP reporter mice
Mice expressing enhanced green fluorescent proteins (eGFP) under the control of the IL-23R (encoded by Il23a) or RORγt (encoded by Rorc) promoter. These mice can be used to track the differentiation, proliferation, migration and effector function of IL-17-producing cells. Gene targeting vectors are generated by introducing eGFP sequences into bacterial artificial chromosome (BAC) clones containing the Il23a or Rorc gene. The targeting constructs are introduced into embryonic stem cells and injected into mouse blastocysts to generate eGFP transgenic mice. The eGFP is co-expressed with IL-23R or RORγt, which allows cell fate analysis of IL-17-producing cells during an immune response.
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Cua, D., Tato, C. Innate IL-17-producing cells: the sentinels of the immune system. Nat Rev Immunol 10, 479–489 (2010). https://doi.org/10.1038/nri2800
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