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

Emilie V. Russler-Germain, Jisun Jung, Aidan T. Miller, Shannon Young, Jaeu Yi, Alec Wehmeier, Lindsey E. Fox, Kristen J. Monte, Jiani N. Chai, Devesha H. Kulkarni, Lisa J. Funkhouser-Jones, Georgia Wilke, Vivek Durai, Bernd H. Zinselmeyer, Rafael S. Czepielewski, Suellen Greco, Kenneth M. Murphy, Rodney D. Newberry, L. David Sibley, Chyi Song Hsieh

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

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 IFN-γ-producing Th1 response. TCR sequencing coupled with in vitro and in vivo analysis of common Th1 TCRs revealed that Ct-STL elicited a dominant antigen-specific Th1 response. In 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.

Original languageEnglish
Pages (from-to)2547-2564.e7
JournalImmunity
Volume54
Issue number11
DOIs
StatePublished - Nov 9 2021

Keywords

  • IFNγ
  • IL-12
  • T cell differentiation
  • TCR sequencing
  • Th1
  • cDC1
  • commensal protist
  • cryptosporidiosis
  • cryptosporidium
  • dendritic cell
  • intestine
  • microbiome

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