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

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.

SUBMITTER: Riding AM

PROVIDER: S-EPMC9283510 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

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

Riding Alexandra M AM Loudon Kevin W KW Guo Andrew A Ferdinand John R JR Lok Laurence S C LSC Richoz Nathan N Stewart Andrew A Castro-Dopico Tomas T Tuong Zewen Kelvin ZK Fiancette Remi R Bowyer Georgina S GS Fleming Aaron A Gillman Eleanor S ES Suchanek Ondrej O Mahbubani Krishnaa T KT Saeb-Parsy Kourosh K Withers David D Dougan Gordan G Clare Simon S Clatworthy Menna R MR

iScience 20220622 7

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 in ...[more]

PMID: 35845169

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Project description:Newborns require early generation of effective innate immunity as a primary physiological mechanism for survival. The neonatal Lin28+Let7- developmental pathway allows increased generation of Th2-type cells and B1a (B-1 B) cells compared to adult cells and long-term maintenance of these initially generated innate cells. For initial B1a cell growth from the neonatal to adult stage, Th2-type IL-5 production from ILC2s and NKT2 cells is important to increase B1a cells. The Th17 increase is dependent on extracellular bacteria, and increased bacteria leads to lower Th2-type generation. Secreted group IIA-phospholipase A2 (sPLA2-IIA) from the Pla2g2a gene can bind to gram-positive bacteria and degrade bacterial membranes, controlling microbiota in the intestine. BALB/c mice are Pla2g2a+, and express high numbers of Th2-type cells and B1a cells. C57BL/6 mice are Pla2g2a-deficient and distinct from the SLAM family, and exhibit fewer NKT2 cells and fewer B1a cells from the neonatal to adult stage. We found that loss of Pla2g2a in the BALB/c background decreased IL-5 from Th2-type ILC2s and NKT2s but increased bacterial-reactive NKT17 cells and MAIT cells, and decreased the number of early-generated B1a cells and MZ B cells and the CD4/CD8 T cell ratio. Low IL-5 by decreased Th2-type cells in Pla2g2a loss led to low early-generated B1a cell growth from the neonatal to adult stage. In anti-thymocyte/Thy-1 autoreactive μκ transgenic (ATAμκ Tg) Pla2g2a+ BALB/c background C.B17 mice generated NKT2 cells that continuously control CD1d+ B1 B cells through old aging and lost CD1d in B1 B cells generating strong B1 ATA B cell leukemia/lymphoma. Pla2g2a-deficient ATAμκTg C57BL/6 mice suppressed the initial B1a cell increase, with low/negative spontaneous leukemia/lymphoma generation. These data confirmed that the presence of Pla2g2a to control bacteria is important to allow the neonatal to adult stage. Pla2g2a promotes innate Th2-type immunity lymphocytes to increase early generated B1a cells.

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

Publications

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

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