Stem-like T cells are associated with the pathogenesis of ulcerative colitis in humans. [scRNAseq_MouseLPL]

To understand the role of T cells in the pathogenesis of ulcerative colitis (UC), we analyzed colonic T cells isolated from UC patients and controls. We identified colonic CD4+ and CD8+ T lymphocyte subsets with gene expression profiles resembling stem-like progenitors, previously reported in animal models of diabetes and other contexts. Stem-like T cells were increased in inflamed areas compared to non-inflamed regions from the same patients. Furthermore, TCR sequence analysis indicated stem-like T cells were clonally related to pro-inflammatory T cells, suggesting their involvement in sustaining effectors that drive inflammation. Using an adoptive transfer colitis model, we demonstrated that CD4+ T cells deficient in BCL-6, a transcription factor promoting T cell stemness, had decreased colon T cells, reduced TH17 cells, and diminished pathogenicity. Our results establish a strong association between stem-like T cell populations and UC pathogenesis, highlighting the potential of targeting this population to improve clinical outcomes. Overall design: In the adoptive T cell transfer model of colitis, 1 x 105 splenic wildtype naïve CD4+CD45RBhighCD25- T cells and 5 x 105 splenic TCRb+CD8b+CD4- T cells from Bcl6fl/flCd8aCre mice or Bcl6fl/fl mice were transferred into Rag1 KO mice. 6-10 weeks later, CD8+ T cells were isolated form mouse colon lamina propria for single cell RNA seq analysis.