Commensal Cryptosporidium colonization elicits a cDC1-dependent Th1 response that promotes intestinal homeostasis and restricts other infections

• Published in: Immunity (Cambridge, Mass.) Mass.), 2021-10, Vol.54 (11), p.2547-2564.e7
• Main Authors: Russler-Germain, Emilie V., Jung, Jisun, Miller, Aidan T., Young, Shannon, Yi, Jaeu, Wehmeier, Alec, Fox, Lindsey E., Monte, Kristen J., Chai, Jiani N., Kulkarni, Devesha H., Funkhouser-Jones, Lisa J., Wilke, Georgia, Durai, Vivek, Zinselmeyer, Bernd H., Czepielewski, Rafael S., Greco, Suellen, Murphy, Kenneth M., Newberry, Rodney D., Sibley, L. David, Hsieh, Chyi-Song
• Format: Article
• Language: English
• ISSN: 1074-7613; 1097-4180
• DOI: 10.1016/j.immuni.2021.10.002

Cryptosporidium can cause severe diarrhea and morbidity, but many infections are asymptomatic. Here, we studied the immune response to a commensal strain of Cryptosporidium tyzzeri ( Ct -STL) serendipitously discovered when conventional type 1 dendritic cell (cDC1)-deficient mice developed cryptosporidiosis. Ct -STL was vertically transmitted without negative health effects in wild-type mice. Yet, Ct -STL provoked profound changes in the intestinal immune system, including induction of an IFNγ-producing Th1 response. T cell receptor sequencing coupled with in vitro and in vivo analysis of common Th1 TCRs revealed that Ct -STL elicited a dominant antigen-specific Th1 response. By contrast, deficiency in cDC1s skewed the Ct -STL CD4 T cell response toward Th17 and regulatory T cells. Although Ct -STL predominantly colonized the small intestine, colon Th1 responses were enhanced and associated with protection against Citrobacter rodentium infection and exacerbation of dextran sodium sulfate and anti-IL10R-triggered colitis. Thus, Ct -STL represents a commensal pathobiont that elicits Th1-mediated intestinal homeostasis that may reflect asymptomatic human Cryptosporidium infection. Cryptosporidium are protozoan parasites that cause gastrointestinal illness in humans and animals worldwide. We identified a commensal strain of Cryptosporidium tyzzeri endemic in our mouse colony. This strain of Cryptosporidium does not cause disease in wild-type mice but changes the composition and function of the intestinal immune system.