Commensal Cryptosporidium colonization drives cDC1-dependent intestinal Th1 mediated homeostasis

Cryptosporidium is an important cause of infectious diarrhea; however, asymptomatic infections are not well characterized. Here, we studied the immunologic response to a commensal strain of Cryptosporidium tyzzeri (Ct-STL) serendipitously discovered when conventional type 1 dendritic cell (cDC1)-deficient mice developed fulminant cryptosporidiosis. We confirmed that Ct-STL behaved as a commensal in wild-type mice, as it was vertically transmitted with minimal deleterious health effects. Yet, Ct-STL provoked profound innate and adaptive changes in the intestinal immune system and induced a strong Ct-STL-specific Th1 cell response. cDC1s were critical for directing Th1 adaptive immunity, as cDC1-deficient mice skewed the Ct-STL response to Th17/Treg cell development. Although Ct-STL predominantly colonized the small intestine, colonic Th1 responses were also enhanced and were associated with protection against Citrobacter rodentium infection and exacerbation of dextran sodium sulfate/anti-IL10R colitis. Thus, Ct-STL represents a novel commensal pathobiont that elicits Th1-mediated homeostasis and exerts substantial effects on mucosal immunity of both the small and large intestine, and may reflect asymptomatic human Cryptosporidium infection.