A highly polarized TH2 bladder response to infection promotes epithelial repair at the expense of preventing new infections

Abstract

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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Fig. 1: Il4−/− but not Ifng−/− mice initiate bacterial clearance within three days after bladder infection.
Fig. 2: CD4+ T cells are preferentially differentiated into TH2 cells in the bladder, particularly after a second infection.
Fig. 3: TH2 cells are necessary for superficial bladder epithelium regeneration.
Fig. 4: IL-4-regulated growth factors are important for epithelial repair.
Fig. 5: Tissue resident CD301b+ dendritic cells activate TH2 cells during bladder infection.
Fig. 6: OX40L on CD301b+ DCs is responsible for the induction of TH2 bias in bladder.
Fig. 7: Repeated bladder infections promote TH2-mediated bladder epithelium repair at the expense of bacterial clearance.

Data availability

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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Acknowledgements

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.

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Studies were designed by J.W. and S.N.A. with help from R.L.R., J.T.P., F.M.H. and Y.M. Experiments were performed by J.W., B.W.H., C.P., G.S.M. and H.W.C. Data were analyzed by J.W. and S.N.A. The manuscript was written by J.W. and S.N.A. All authors contributed to discussions and manuscript review.

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Correspondence to Soman N. Abraham.

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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

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