Autoimmunity and infection give rise to distict inflammatory Th17 subsets [single-cell RNA-seq]

Th17 cells are a heterogeneous population that is critical for tissue homeostasis and inflammation during clearance of infections and autoimmunity. Despite substantial efforts distinguishing homeostatic and inflammatory roles of Th17 cells, the mechanism underlying the divergent functions of inflammatory Th17 cells is poorly understood. In this study, we show that the inflammatory Th17 engaged in autoimmune colitis and those involved in infection-induced colitis are two distinguishable populations illustrated by their distinct responses to a pharmacological molecule, clofazimine (CLF). Distinct from existing Th17 inhibitors, CLF selectively inhibits pro-autoimmune Th17 cells while preserving the functional state of infection-elicited Th17 cells through restricting Aldh1l2expression. Using single-cell RNA sequencing, we explored inflammatory Th17 transcriptional response to CLF from the colonic tissue of mice during autoimmune colitis and Citrobacter rodentiuminfection using Rorc gfp/+ reportor mice. Notably, we identified a unique suppression in the transcription of signature inflammatory genes in Th17 cells from autoimmune colitis with a marginal effect on those elicited by infection. Additionally, we illustrate with these data that the transcriptionally programming of pro-autoimmune Th17 cells are, indeed, unique compared to infection-elicited Th17 cells. Finally, we analyzed the impact of CLF on human inflammatory Th17 cells from the inflammed colon of a patient with IBD. Overall design: Using single-cell RNA sequencing, we explored inflammatory Th17 transcriptional response to CLF from the colonic tissue of mice during autoimmune colitis and Citrobacter rodentiuminfection using Rorc gfp/+ reportor mice. Notably, we identified a unique suppression in the transcription of signature inflammatory genes in Th17 cells from autoimmune colitis with a marginal effect on those elicited by infection. Additionally, we analyzed the impact of CLF on human inflammatory Th17 cells from the inflammed colon of a patient with IBD.