Peripheral blood MAIT cell response to enterotoxigenic E. coli strains H10407 and B7A after controlled human infection models (CHIMs)

Abstract Mucosal associated invariant T (MAIT) cells are an unconventional T cell subset with a semi-invariant TCR that recognizes microbially-derived riboflavin metabolites and elicit broad antimicrobial activity. MAIT cells are implicated in the control of bacterial infections, however, their role in enterotoxigenic E. coli (ETEC) infection, a common cause of traveler’s diarrhea, is unknown. Using multi-color polychromatic flow cytometry and RNA-seq on sorted peripheral MAIT cells of volunteers orally challenged with ETEC strains H10407 (CFA/I+LT+ST+; median time to first loose stool, mtFLS=47h; n=8) or B7A (CS6+ LT+ST+; mtFLS=13h; n=12), we observed that MAIT cells express higher levels of gut-homing molecules a4b7 and CCR9 7-days post-challenge. Moreover, MAIT cells also have an increase in expression of markers of activation CD38 (p=0.003) and cell proliferation Ki-67 (p=0.01) 7-days post-challenge, despite no change in overall frequency. RNA-seq revealed distinct transcriptional signatures 7-days post challenge in both challenge models. Gene set enrichment analysis (GSEA) showed that challenge with both ETEC strains elicit an upregulation of pathways involved in MAIT cell proliferation and division. Several pathways involving IL-1 secretion and the inflammasome were also upregulated after H10406 challenge. Meanwhile, B7A challenge upregulated innate-like pathways such as Natural Killer Cell Activation. These data suggest that MAIT cells are responding during ETEC challenge with upregulation markers of gut homing, activation and proliferation, but undergo differential means of activation after CHIMs with H10407 compared to the more fact-acting B7A ETEC strain.