A pivotal role for antigen-presenting cells overexpressing SOCS3 in controlling invariant NKT cell responses during collagen-induced arthritis

Abstract

Objective Suppressor of cytokine signalling (SOCS) proteins constitute a class of intracellular proteins that are key physiological regulators of immune cell function. It has previously been shown that antigen-presenting cells (APCs) overexpressing SOCS3 steer T helper immune responses and protect against experimental arthritis. A study was undertaken to investigate the contribution of SOCS3 in regulating invariant natural killer T (iNKT) cell responses during collagen-induced arthritis (CIA). Methods DBA/1 mice were immunised with type II collagen and adenoviruses encoding SOCS3 were administered intravenously before the clinical onset of arthritis. Murine APCs overexpressing SOCS3 were co-cultured with an iNKT cell hybridoma and interleukin 2 (IL-2) release was measured by Luminex multi-analyte technology. The frequency and activation of primary iNKT cells was assessed by fl ow cytometry. Murine APCs were analysed for cytokine and CD1d expression following viral SOCS3 gene transfer. Results Viral overexpression of SOCS3 in APCs resulted in reduced activation of the iNKT cell hybridoma. Importantly, during initiation of CIA, adenovirus-mediated overexpression of SOCS3 in hepatic and splenic APCs inhibited iNKT cell expansion in both organs. The iNKT cell population from SOCS3-treated mice showed low expression of the early activation marker CD69 and primary liver iNKT cells produced less interferon γ and IL-4 upon α-galactosylceramide stimulation. No differences in CD1d surface expression were observed, but SOCS3-transduced APCs produced decreased levels of proinfl ammatory cytokines and increased levels of IL-10. Conclusion These results demonstrate a critical role for SOCS3 in controlling the immunostimulatory capacities of APCs, which has direct implications for the effector function of iNKT cells during arthritis.

Disease-Dependent Local IL-10 Production Ameliorates Collagen Induced Arthritis in Mice

“…The SOCS adaptor proteins are in turn induced by IL-10 [15]. In fact, increased expression of both SOCS1 and 3 have been shown to decrease the severity of arthritis [15], [25], [26]. In our system, increased production of IL-10 in lymph nodes coincides with elevated mRNA levels of SOCS1 and decreased levels of IL-6.…”

Enhanced suppressor of cytokine signaling 3 in arthritic cartilage dysregulates human chondrocyte function

“…Recently, our group showed that intravenously induced overexpression of murine SOCS-3 markedly ameliorated collagen-induced arthritis via modulation of T cell and natural killer T cell responses (8,9). The role of SOCS proteins in mediating inhibition of cytokine and growth factor responses makes the SOCS proteins prime candidates for regulating chondrocyte function during growth and joint diseases.…”

Toll-like receptor 4 in bone marrow-derived cells as well as tissue-resident cells participate in aggravating autoimmune destructive arthritis

“…These cells have been shown to produce vast amounts of IL-17 upon CD3 and IL-23 stimulation,37 and in particular, the NK1.1 − iNKT cells 38. Moreover, the iNKT cells have been shown to be important in experimental arthritis 39. Finally, the γδ T-cells have been shown to produce IL-17 in response to mycobacterium infection40 and IL-23 alone is sufficient to induce IL-17 production in these cells.…”