Rheumatoid arthritis (RA) is the most common systemic autoimmune disease. T helper 17 (Th17) cells are found in the inflamed synovium in RA and believed to play a pathogenic role. However, IL-17 targeted interventions have shown limited efficacy in established RA. Inflammation can induce Th17 transdifferentiation into IL-17 negative Th1 or Tr1 like exTh17. To assess the potential phenotype and role of exTh17 in inflammatory arthritis, we performed Th17 fate mapping studies in the SKG mouse model of RA. We generated triTh17-SKG (IL-17Cre.IfngYFP.Il10eGFP.R26tdTomfl.Zap70SKG) mice and leveraged them to show that in arthritic mice synovial Th17 transdifferentiate into IFNγ- and IL-10- exTh17 which become the most prominent CD4 population in chronic arthritis. These exTh17 cells are more arthritogenic than Th17, and able to sustain arthritis that is IL-17 independent but enriched with IL-6 and TNF, two known RA-promoting cytokines. Synovial exTh17 present a unique gene signature including upregulation of CD44 and S1PR4 that has correlates in the profile of CD4 T cells found in human RA synovium. We further demonstrate that a crosstalk with synoviocytes and S1P signaling promote Th17-exTh17 conversion and that CD44 – another known target for RA- is necessary for the arthritogenic effect of exTh17. Our study suggests that the synoviocyte expansion which occurs during RA progression can drive progressive conversion of Th17 into exTh17, which in turn sustain inflammation that has hallmarks of human established RA.
import lamindb as ln
import spatialdata as sd
coll = ln.Collection.get(key="geo-gse232734")
coll.ordered_artifacts.df() # the 2 members, ordered
# download every member .zarr to the local cache:
paths = [a.cache() for a in coll.ordered_artifacts.all()]
# …or load each straight into memory as a SpatialData object:
sdatas = {a.key: sd.read_zarr(a.cache()) for a in coll.ordered_artifacts.all()}
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