Th17 and regulatory T cells: rebalancing pro- and anti-inflammatory forces in autoimmune arthritis

Abstract

Inflammatory T cells are thought to be central to the pathology of autoimmune arthritis. Th17 cells, CD4 T cells that secrete the pro-inflammatory cytokine IL-17 play a critical role in murine models of arthritis. Recent evidence from human studies suggests that Th17 cells may be important players in several autoimmune diseases, including seronegative arthritis in adults, childhood arthritis [juvenile idiopathic arthritis (JIA)]. It was surprising to find that the development of Th17 cells is closely related to that of an immunoregulatory subset called regulatory T cells (Tregs). Tregs are important in the maintenance of immune homeostasis. Defects in Treg function or reduced numbers have been documented in several human autoimmune diseases, including RA and JIA. Conditions that typically favour the development of Tregs and promote tolerance can be subverted by inflammatory signals towards supporting the generation of Th17 cells. In animal models, the enhancement of Th17 cell differentiation is at the expense of Tregs, and these combined changes trigger autoimmunity. Several mechanisms have come to light that control this reciprocal relationship between Tregs and Th17 cells, including the action of pro-inflammatory cytokines such as IL-1beta. Anti-rheumatic biologic therapies may offer a means of restoring the Th17/Treg balance in favour of Tregs and thereby re-establishing immune tolerance.

Higher infiltration by Th17 cells compared with regulatory T cells is associated with severe acute T-cell-mediated graft rejection

“…In addition, Th17 cells can interconvert with Treg cells depending on the microenvironment (Lee et al, 2009). The imbalance between Th17 and Treg cells has been proposed as an important mechanism that modulates immune responses in various autoimmune disorders (Lee et al, 2009;Nistala and Wedderburn, 2009;Ochs et al, 2009;Eastaff-Leung et al, 2010;Shin et al, 2010).…”

Evidence of the transient nature of the Th17 phenotype of CD4+CD161+ T cells in the synovial fluid of patients with juvenile idiopathic arthritis

“…T cell infiltrates predominantly consist of Th1-skewed cells, which were thought to have a central role in disease pathogenesis (21). After the association between Th17 cells and several human autoimmune diseases, including RA, was observed, some studies found increased levels of IL-17A, as well as the presence of Th17 cells and the expression of their transcription factor, RORC, in the synovial fluid (SF) of children with JIA (22)(23)(24)(25)(26).…”

Hematopoietic Cell Transplantation for Autoimmune Diseases: A Review of History, Current State, and Future Issues

“…Break of tolerance causes accumulation of immune effector cells, including macrophages and osteoclasts, DCs, B and T cells, especially Th17 subsets. Reduced T-cell receptor (TCR) excision circles and shortened telomeres result in a contracted TCR repertoire in both naïve and memory cells [85,86].…”