It Takes “Guts” to Cause Joint Inflammation: Role of Innate-Like T Cells

Abstract

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.

The role of IL-17A in axial spondyloarthritis and psoriatic arthritis: recent advances and controversies

“…Mucosal tissues have also emerged as a key physiological site for the differentiation and regulation of Th17 cells 77 159 160. A role for ILC3 and innate-like T cells such as iNKT cells and MAIT cells in IBD is also postulated based on their high representation at barrier sites 161–163. Putative links have also been suggested between gut inflammation, migration and accumulation of IL-17A-producing ILC3 cells in the joints of patients with AS 164.…”

RORγt inhibition selectively targets IL-17 producing iNKT and γδ-T cells enriched in Spondyloarthritis patients

“…Whether AHR mediated responses are altered is appealing given the increased AHR gene expression we observed in blood circulating iNKT cells in SpA patients. This however warrants additional investigation of innate-like T cells in gut samples from SpA patients 67 .…”

“…Given that IL-17 also mediated protective barrier function in the gut, these data point to a delicate and complex network of pro-inflammatory and anti-inflammatory signals involved in host protection. A shift in these immune processes in susceptible individuals may tip the balance toward disease initiating events in SpA 67 . Whether AHR mediated responses are altered is appealing given the increased AHR gene expression we observed in blood circulating iNKT cells in SpA patients.…”

MAIT Cells Come to the Rescue in Cancer Immunotherapy?

“…In line with this, it has been shown that CD1d-deficient (NKT cell-deficient) mice exhibit increased numbers of MAIT cells (and vice versa) [2]. However, despite vast interindividual differences in MAIT and iNKT cell abundance, the ratio of the two populations across human blood samples seems to be constant in health (and sometimes disease), suggesting they are also controlled by similar genetic and/or environmental factors, at least in the periphery [41,46,47]. Altogether, the multi-level resemblance leads to the idea that MAIT and iNKT cells are complementarily bridging innate and adaptive immunity, and this interdependence is tightly regulated by common developmental or homeostatic factors while retaining their specific role in non-peptide TCR mediated immune responses.…”

“…Studies on MAIT cell development and effector functions point towards their close relationship with another unconventional T cell population, the invariant natural killer T cells [41] (Table 1). Invariant natural killer T cells (iNKT) cells express a semi-invariant αβTCR (human Vα24/Jα18 combined with Vβ11, mice Vα14-Jα18 combined with Vβ2, Vβ7, or Vβ8.2), which allows them to recognize lipid antigens presented by CD1d molecules [42].…”