ICOS Signaling Controls Induction and Maintenance of Collagen-Induced Arthritis

Abstract

ICOS is a key costimulatory receptor facilitating differentiation and function of follicular helper T cells and inflammatory T cells. Rheumatoid arthritis patients were shown to have elevated levels of ICOS T cells in the synovial fluid, suggesting a potential role of ICOS-mediated T cell costimulation in autoimmune joint inflammation. In this study, using ICOS knockout and knockin mouse models, we found that ICOS signaling is required for the induction and maintenance of collagen-induced arthritis (CIA), a murine model of rheumatoid arthritis. For the initiation of CIA, the Tyr-based SH2-binding motif of ICOS that is known to activate PI3K was critical for Ab production and expansion of inflammatory T cells. Furthermore, we found that Tyr-dependent ICOS signaling is important for maintenance of CIA in an Ab-independent manner. Importantly, we found that a small molecule inhibitor of glycolysis, 3-bromopyruvate, ameliorates established CIA, suggesting an overlap between ICOS signaling, PI3K signaling, and glucose metabolism. Thus, we identified ICOS as a key costimulatory pathway that controls induction and maintenance of CIA and provide evidence that T cell glycolytic pathways can be potential therapeutic targets for rheumatoid arthritis.

Glucose transporter 1 in rheumatoid arthritis and autoimmunity

“…3‐bromopyruvate also improved arthritis in the SKG model probably via induction of Tregs and reductions in dendritic cells as shown in isolated splenocytes (Okano et al, ). Similar results were obtained with 3‐bromopyruvate (Figure ) in a collagen‐induced arthritis model (Panneton, Bagherzadeh Yazdchi, Witalis, Chang, & Suh, ). Abboud et al tested 2‐DG, a competitive inhibitor of hexokinase, in the serum induced arthritis model and observed improved joint inflammation and reduced development of pathogenic autoantibodies in a preventive treatment scheme (Abboud et al, ).…”

Inducible T‐cell co‐stimulator: Signaling mechanisms in T follicular helper cells and beyond

“…In autoimmune disease models, ICOS has been shown to play important roles in supporting the pathogenic functions of Teff cells. We have shown that ICOS signaling is critical for the induction and maintenance of collagen‐induced arthritis . As expected, ICOS‐PI3K signaling is critical to induce pathogenic antibodies during the disease induction phase.…”

“…This is consistent with its minimal impact on initial T‐cell expansion in ICOS‐deficient mice . Despite the overall similarities in the T‐cell stimulatory functions shared between ICOS and CD28, ICOS has critical non‐redundant functions in multiple immune responses …”

“…Instead, CD28 co‐stimulation seems to heavily rely on other signaling motifs such as SH3‐binding proline‐rich motifs . In contrast, selective abrogation of the ICOS‐PI3K signaling resulted in strong defects in Tfh generation, autoimmune joint inflammation, acute graft‐vs‐host disease (GVHD), chlamydial lung infection, and anti‐tumor T‐cell responses . Another signaling mechanism unique to ICOS is TBK1 .…”

“…In addition to antigen‐presenting cells, ICOSL has been found to be inducibly expressed on fibroblasts, endothelial cells, epithelial cells, muscle fibers, and podocytes under inflammatory conditions. Thus, ICOS co‐stimulation can dominate under situations where CD28 ligands are limited such as in inflamed tissues . Importantly, ICOS and ICOSL, but not CD28 and its ligands, are expressed on ILCs .…”