Interleukin-23 and T helper 17-type responses in intestinal inflammation: from cytokines to T-cell plasticity

Abstract

Summary Interleukin‐23 (IL‐23) plays an essential role in driving intestinal pathology in experimental models of both T‐cell‐dependent and innate colitis. Furthermore, genome‐wide association studies have identified several single‐nucleotide polymorphisms in the IL‐23 receptor (IL‐23R) gene that are associated with either susceptibility or resistance to inflammatory bowel disease in humans. Although initially found to support the expansion and maintenance of CD4+ T helper 17 (Th17) cells, IL‐23 is now recognized as having multiple effects on the immune response, including restraining Foxp3+ regulatory T‐cell activity and inducing the expression of Th17‐type cytokines from non‐T‐cell sources. Here we focus on Th17 cells and their associated cytokines IL‐17A, IL‐17F, IL‐21 and IL‐22. We review studies performed in mouse models of colitis where these effector cytokines have been shown to have either a pathogenic or a tissue‐protective function. We also discuss the heterogeneity found within the Th17 population and the phenomenon of plasticity of Th17 cells, in particular the ability of these lymphocytes to extinguish IL‐17 expression and turn on interferon‐γ production to become Th1‐like ‘ex‐Th17’ cells. Interleukin‐23 has been identified as a key driver in this process, and this may be an additional mechanism by which IL‐23 promotes pathology in the intestinal tract. These ‘ex‐Th17’ cells may contribute to disease pathogenesis through their secretion of pro‐inflammatory mediators.

Human Th17 Cells Express High Levels of Enzymatically Active Dipeptidylpeptidase IV (CD26)

“…Our finding that CD26 ++ IL-17-producing T cells are highly enriched in the inflamed tissues compared with the peripheral blood (Fig. 6C, 6D) is in agreement with previous studies implicating a role of Th17 cells in the pathogenesis of these inflammatory diseases (26,35), particularly inflammatory bowel disease (36). Interestingly, high levels of CD26 have previously been associated with autoimmune diseases, such as multiple sclerosis and rheumatoid arthritis (10,11).…”

Differential Requirements for IL-17A and IL-22 in Cecal versus Colonic Inflammation Induced by Helicobacter hepaticus

“…With respect to the gastrointestinal tract, elevated levels of IL-17A, IL-17F, IL-21, and IL-22 have been found in both the inflamed intestine of humans with IBD and in experimental models of the disease. 8 Although IL-17A can promote proinflammatory responses through the induction of neutrophilattracting chemokines and matrix metalloproteinases, 9 we herein demonstrate that H. hepaticuseinduced typhlitis is exacerbated when IL-17A is neutralized, suggesting an anti-inflammatory role for this cytokine in T-celledriven bacteria-induced intestinal inflammation. Consistent with our findings, previous studies have reported exacerbation of dextran sulphate sodium colitis in the absence of IL-17A, through either antieIL-17A mAb treatment or the use of IL-17A À/À mice.…”

“…IL-23, which is crucial for driving both cecal and colonic inflammation in H. hepaticuseinfected hosts, 28 has multiple functions in the immune system, including promoting Th17-type cytokine secretion by T-and noneT-cell sources, inhibiting the differentiation of induced T-regulatory cells, and indirectly restraining IL-10 production by CD4 þ T cells. 8 As such, IL-23 may be an additional driver of pathology in the cecum that overrides the effect of IL-22 blockade. Although we did not find any difference in Il23a transcript levels between the cecum and colon, we observed enhanced mRNA levels of both Il12b and Il23r in the cecum compared with the colon, suggesting that the former tissue may be more responsive to IL-23.…”

“…5 IL-23 is produced by activated dendritic cells and macrophages after microbial stimulation, 6,7 and one of its many functions is the enhancement of CD4 þ type 1 helper T-cell (Th1) and type 17 helper T-cell (Th17) responses and the induction of Th1/Th17-type cytokines by noneT-cell sources. 8 Increased levels of both Th1-[interferon (IFN)-g] and Th17-type cytokines (IL-17A, IL-17F, and IL-22) are found in inflamed tissues in both human IBD and experimental models of the disease, 8 but the importance of these cytokines in disease pathogenesis at different anatomical locations of the gut is not well characterized.…”

“…8,9 The receptor for IL-17A and IL-17F is composed of IL-17RA and IL-17RC, and is expressed on both hematopoietic and nonhematopoietic cells. 10 In contrast, the receptor for IL-22, a heterodimer composed of IL-22 receptor a1 (IL-22Ra1) and IL-10Rb2, 11,12 is found on nonhematopoietic cells.…”