The human appendix is a unique inductive site for pathogenic CD8+ T cells in ulcerative colitis 2559

Description The appendix is a secondary lymphoid organ that shows increased T cell activation in ulcerative colitis (UC), but not in Crohn’s disease (CD) or colorectal cancer (CRC). As people with prior appendectomy rarely develop UC, excision of the appendix may lower disease risk – potentially because it eliminates a major source of pathogenic T cells that fuels inflammation in the colon. To explore this possibility, we used scRNA-seq with scTCR-seq and antigen-prediction tools to profile lymphoid and/or colonic tissues from UC, CD, and CRC patients. We found that the UC appendix is enriched in clonally expanded effector CD8+ T cells with a distinct proinflammatory Granzyme K (GZMK)+ signature, the repertoire of which is skewed towards viral antigens known to persist in the gut mucosa. These cells are rare in the regional lymph nodes but are present in the UC colon. In fact, immunofluorescence staining confirmed that GZMK+ CD8+ T cells are abundant in the inflamed (but not uninflamed) UC colon. Notably, in the rare appendectomy patients who later develop UC, these T cells are depleted from the inflamed colon, providing the first evidence that the appendix is a unique inductive site for pathogenic CD8+ T cells in UC. Indeed, comparison of spatially resolved transcriptional features of the colonic epithelium in UC segregated patients with and without prior appendectomy, revealing appendix-dependent and -independent mechanisms of disease. Funding Sources The work was supported by NIDDK P30DK042086; T32DK007074; T32AI007090 Topic Categories Mucosal and Regional Immunology (MUC)