The objective of this grant application is to explore the plasticity of Th17 in arthritis. Interleukin-17A (IL-17A) producing Th17 are present often in large numbers in the synovium of patients with rheumatoid and psoriatic arthritis. However, targeting of IL17A is generally insufficient to fully control joint inflammation in these conditions. One potential scenario is that in the context of worsening joint inflammation, Th17 undergo conversion into pathogenic IL17A-negative cell populations, collectively called exTh17. The conversion of Th17 into exTh17 has been documented in the context of neuroinflammation and infections, and locally produced IL-7 was described as a key promoter of Th17 plasticity in the lung. However, the occurrence of Th17 plasticity in arthritis and its potential role in perpetuating synovial inflammation remain unknown. We generated a novel fate-mapping mouse model of autoimmune arthritis, which allows to follow the conversion of Th17 into exTh17, and collected preliminary data suggesting that Th17 undergo significant loss of IL17A expression and conversion into exTh17 in the context of synovial inflammation. We also identified candidate exTh17 subpopulations which might contribute to perpetuate joint inflammation despite their loss of IL17A expression. Here we will leverage our mouse model to collect pilot evidence about the immunoregulatory and/or pathogenic role of exTh17 in synovial autoimmune inflammation (Aim 1). Also, we will explore whether IL-7 or other factors produced by synovial fibroblast play a role in inducing conversion of Th17 into exTh17 (Aim 2). Our long-term goal is to leverage knowledge of local immune cell phenotypes at various stages of disease to enable stage-specific and personalized therapies of arthritis to minimize non specific immunosuppression.
Immune cell populations that cause arthritis can acquire novel gene patterns and morph into different populations under the effect of local inflammation in the joints. To explore of this phenomenon, we have generated genetically manipulated mice that allow to assess the local fate of a specific arthritogenic immune population called Th17 and have observed that Th17 morph into different populations once arthritis is established. In this grant we will leverage this new mouse model to understand whether these new populations contribute to joint inflammation and what local factors promote local changes in behavior of Th17 in arthritis.
