Dysregulated IL-23/IL-17 responses have been linked to psoriatic arthritis and other forms of spondyloarthritides (SpA). RORγt, the key Thelper17 (Th17) cell transcriptional regulator, is also expressed by subsets of innate-like T cells, including invariant natural killer T (iNKT) and γδ-T cells, but their contribution to SpA is still unclear. Here we describe the presence of particular RORγt+T-betloPLZF− iNKT and γδ-hi T cell subsets in healthy peripheral blood. RORγt+ iNKT and γδ-hi T cells show IL-23 mediated Th17-like immune responses and were clearly enriched within inflamed joints of SpA patients where they act as major IL-17 secretors. SpA derived iNKT and γδ-T cells showed unique and Th17-skewed phenotype and gene expression profiles. Strikingly, RORγt inhibition blocked γδ17 and iNKT17 cell function while selectively sparing IL-22+ subsets. Overall, our findings highlight a unique diversity of human RORγt+ T cells and underscore the potential of RORγt antagonism to modulate aberrant type 17 responses.
Innate-like T cells such as invariant natural killer T (iNKT) cells and mucosal-associated T (MAIT) cells, characterized by a semi-invariant T cell receptor and restriction toward MHC-like molecules (CD1 and MR1 respectively), are a unique unconventional immune subset acting at the interface of innate and adaptive immunity. Highly represented at barrier sites and capable of rapidly producing substantial amounts of cytokines, they serve a pivotal role as first-line responders against microbial infections. In contrast, it was demonstrated that innate-like T cells can be skewed toward a predominant pro-inflammatory state and are consequently involved in a number of autoimmune and inflammatory diseases like inflammatory bowel diseases and rheumatic disorders, such as spondyloarthritis (SpA) and rheumatoid arthritis. Interestingly, there is link between gut and joint disease as they often co-incide and share certain aspects of the pathogenesis such as established genetic risk factors, a critical role for pro-inflammatory cytokines, such as TNF-α, IL-23, and IL-17 and therapeutic susceptibility. In this regard dysregulated IL-23/IL-17 responses appear to be crucial in both debilitating pathologies and innate-like T cells likely act as key player. In this review, we will explore the remarkable features of iNKT cells and MAIT cells, and discuss their contribution to immunity and combined gut–joint disease.
Spondyloarthritis (SpA) encompasses a group of diseases characterized by an inflammatory arthritis involving both joints and entheses. However, extraarticular symptoms constitute a large element of the pathology and should not be underestimated. Microscopic gut inflammation is observed in 50% of patients with SpA and has been linked to disease activity, underscoring the effect of gut inflammation in SpA. In this review, we discuss the influence of gut microbiota on SpA pathogenesis. A change in microbiota composition has been linked to the development of various inflammatory arthritides, and dysbiosis is a potential factor in the pathogenesis of multiple inflammatory diseases. In this context, several groups have reported the modulatory effects of gut microbiota-derived metabolites on the effect of immune cells. The gut mucosa is populated by several types of regulatory T cells, but also some specialized unconventional innate-like T cells. These cells are predominantly found at mucosal and epithelial barrier sites, where they serve an essential role in modulating host-microbial interplay. Apart from the close association between the composition of the microbiota and inflammatory diseases, the therapeutic value of dysbiosis needs further investigation, and the identification of a causal inflammatory pathway between gut dysbiosis and musculoskeletal inflammation could revolutionize the therapeutic approach in SpA.
Objective Divergent therapeutic outcomes on different disease domains have been noted with interleukin (IL)-23 and IL-17A-blockade in psoriatic arthritis (PsA). Therefore, elucidating the role of RORγt, the master regulator of type 17 immune responses, is of potential therapeutic interest. To this end, RORγt inhibition was assessed in combined skin, joint and gut inflammation in vivo, using a PsA model. Methods We tested the efficacy of a RORγt antagonist in B10.RIII mice challenged with systemic overexpression of IL-23 by hydrodynamic injection of IL-23 enhanced episomal vector (IL-23 EEV). Clinical outcomes were evaluated by histopathology. Bone density and surface erosions were examined using micro-computed tomography. Cytokine production was measured in serum and by intracellular flow cytometry. Gene expression in PsA-related tissues was analysed by qPCR. Results RORγt-blockade significantly ameliorated psoriasis, peripheral arthritis and colitis development in IL-23 EEV mice (improvement of clinical scores and weight loss respectively by 91.8%, 58.2% and 7.0%, p< 0.001), in line with profound suppression of an enhanced type IL-17 immune signature in PsA-affected tissues. Moreover, inflammation-induced bone loss and bone erosions were reduced (p< 0.05 in calcaneus, p< 0.01 in tibia). Sustained IL-23 overexpression resulted in only mild signs of sacroiliitis. Gamma-delta (γδ)-T cells, the dominant source of T cell-derived IL-17A and IL-22, were expanded during IL-23 overexpression, and together with Th17 cells, clearly countered by RORγt inhibition (p< 0.001). Conclusion RORγt-blockade shows therapeutic efficacy in a preclinical PsA model with protection towards extra-musculoskeletal manifestations, reflected by a clear attenuation of type 17 cytokine responses by γδ-T cells and Th17 cells.
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