Urinary tract infections (UTIs) typically evoke prompt and vigorous innate bladder immune responses, including extensive exfoliation of the epithelium. To explain the basis for the extraordinarily high recurrence rates of UTIs, we examined adaptive immune responses in mouse bladders. We found that, following each bladder infection, a highly T helper type 2 (TH2)–skewed immune response directed at bladder re-epithelialization is observed, with limited capacity to clear infection. This response is initiated by a distinct subset of CD301b+OX40L+ dendritic cells, which migrate into the bladder epithelium after infection before trafficking to lymph nodes to preferentially activate TH2 cells. The bladder epithelial repair response is cumulative and aberrant as, after multiple infections, the epithelium was markedly thickened and bladder capacity was reduced relative to controls. Thus, recurrence of UTIs and associated bladder dysfunction are the outcome of the preferential focus of the adaptive immune response on epithelial repair at the expense of bacterial clearance.
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All data supporting the findings of this study are available within the article and its supplementary information and from the corresponding author upon reasonable request.
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We thank R. Locksley for providing the reporter strains. We thank the Duke Light Microscopy Core Facility, especially Y. Gao, for their expertise and advice in light microscopy imaging. We thank the Flow Cytometry Shared Resource of the Duke Cancer Institute for their assistance with flow cytometry analysis. We also appreciate the help of M.-N. Huang in the design of the flow cytometry panel. The authors acknowledge the support of the US National Institutes of Health grants R01DK121032 and R01DK121969 to S.N.A.
The authors declare no competing interests.
Peer review information Ioana Visan was the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.
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Wu, J., Hayes, B.W., Phoenix, C. et al. A highly polarized TH2 bladder response to infection promotes epithelial repair at the expense of preventing new infections. Nat Immunol 21, 671–683 (2020). https://doi.org/10.1038/s41590-020-0688-3
Nature Immunology (2020)