Group 3 innate lymphocytes make a distinct contribution to type 17 immunity in bladder defence

Alexandra M Riding; Kevin W Loudon; Andrew Guo; John R Ferdinand; Laurence S C Lok; Nathan Richoz; Andrew Stewart; Tomas Castro-Dopico; Zewen Kelvin Tuong; Remi Fiancette; Georgina S Bowyer; Aaron Fleming; Eleanor S Gillman; Ondrej Suchanek; Krishnaa T Mahbubani; Kourosh Saeb-Parsy; David Withers; Gordan Dougan; Simon Clare; Menna R Clatworthy

doi:10.1016/j.isci.2022.104660

Group 3 innate lymphocytes make a distinct contribution to type 17 immunity in bladder defence

iScience. 2022 Jun 22;25(7):104660. doi: 10.1016/j.isci.2022.104660. eCollection 2022 Jul 15.

Authors

Alexandra M Riding^{1

2}, Kevin W Loudon^{1

2}, Andrew Guo^{1

2

3}, John R Ferdinand^{1

2}, Laurence S C Lok^{1

2}, Nathan Richoz^{1

2}, Andrew Stewart^{1

2}, Tomas Castro-Dopico^{1

2}, Zewen Kelvin Tuong^{1

2

3}, Remi Fiancette⁴, Georgina S Bowyer^{1

2}, Aaron Fleming^{1

2}, Eleanor S Gillman^{1

2}, Ondrej Suchanek^{1

2}, Krishnaa T Mahbubani⁵, Kourosh Saeb-Parsy^{5

6

7}, David Withers⁴, Gordan Dougan², Simon Clare², Menna R Clatworthy^{1

2

3

6

7}

Affiliations

¹ Molecular Immunity Unit, University of Cambridge Department of Medicine MRC Laboratory of Molecular Biology, Cambridge Biomedical Campus, Francis Crick Avenue, Cambridge CB2 0QH, UK.
² Cambridge Institute for Therapeutic Immunology and Infectious Diseases (CITIID), Jeffrey Cheah Biomedical Centre, Cambridge Biomedical Campus, Puddicombe Way, Cambridge CB2 0AW, UK.
³ Cellular Generics, Wellcome Sanger Institute, Hinxton, UK.
⁴ Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
⁵ University of Cambridge Department of Surgery, Cambridge, UK.
⁶ NIHR Cambridge Biomedical Research Centre, Cambridge, UK.
⁷ Parasites and Microbes, Wellcome Sanger Institute, Hinxton, UK.

Abstract

Bladder infection affects a hundred million people annually, but our understanding of bladder immunity is incomplete. We found type 17 immune response genes among the most up-regulated networks in mouse bladder following uropathogenic Escherichia coli (UPEC) challenge. Intravital imaging revealed submucosal Rorc+ cells responsive to UPEC challenge, and we found increased Il17 and IL22 transcripts in wild-type and Rag2 ^-/- mice, implicating group 3 innate lymphoid cells (ILC3s) as a source of these cytokines. NCR-positive and negative ILC3 subsets were identified in murine and human bladders, with local proliferation increasing IL17-producing ILC3s post infection. ILC3s made a more limited contribution to bladder IL22, with prominent early induction of IL22 evident in Th17 cells. Single-cell RNA sequencing revealed bladder NCR-negative ILC3s as the source of IL17 and identified putative ILC3-myeloid cell interactions, including via lymphotoxin-β-LTBR. Altogether, our data provide important insights into the orchestration and execution of type 17 immunity in bladder defense.

Keywords: Cell biology; Immunology; Transcriptomics.

Grants and funding

MR/N024907/1/MRC_/Medical Research Council/United Kingdom