Pro-inflammatory NK-like T cells are expanded in the blood and inflamed intestine in Crohn's disease.

Altered intestinal immune homeostasis leads to chronic inflammation in Crohn's disease (CD). To address disease- and tissue-specific alterations, we performed a T cell-centric mass cytometry analysis of peripheral and intestinal lymphocytes from patients with CD and healthy donors' PBMCs. Chronic intestinal inflammation enforced activation, exhaustion, and terminal differentiation of CD4⁺ and CD8⁺ T cells and a relative enrichment of CD4⁺ regulatory T (Treg) cells. Moreover, enigmatic rare Treg subsets appeared upon inflammation, e.g. CD4⁺FOXP3⁺HLA-DR⁺TIGIT^- and CD4⁺FOXP3⁺CD56⁺, expressing pro-inflammatory IFN-γ upon in vitro stimulation. Some conventional T (Tcon) cells acquired NK-like features. In CD patients' blood, not well studied CD16⁺CCR6⁺CD127⁺ T cells appeared, being CD4⁺ or CD8⁺, a phenotype inducible on healthy T cells by CD blood plasma. Upon CD16-mediated antibody binding, they could attain effector function. These findings suggest an uncommon pro-inflammatory innate-like differentiation of Treg and Tcon cells with acquisition of non-specific cytotoxicity. Most likely, this is both cause and consequence of intestinal inflammation during CD.