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Spatial Distribution of LTi-like Cells in Intestinal Mucosa Regulates Type 3 Innate Immunity

ABSTRACT: Lymphoid tissue inducer (LTi)-like cells are tissue resident innate lymphocytes that rapidly secrete cytokines that promote gut epithelial integrity and protect against extracellular bacterial infections. Here we report that the retention of LTi-like cells in conventional solitary intestinal lymphoid structures (SILT) is essential for controlling LTi-like cell function and is maintained by expression of the chemokine receptor CXCR5. Deletion of Cxcr5 functionally unleashed LTi-like cells in a cell intrinsic manner, leading to uncontrolled IL-17 and IL-22 production. The elevated production of IL-22 in Cxcr5-deficient mice improved gut barrier integrity, and protected mice during infection with the opportunistic pathogen Clostridium difficile. Interestingly, Cxcr5-/- mice developed LTi-like cell aggregates that were displaced from their typical niche at the intestinal crypt, and LTi-like cell hyperresponsiveness was associated with the local formation of these unconventional SILT. Thus, LTi-like cell positioning within mucosa controls their activity via niche-specific signals that temper cytokine production during homeostasis

ORGANISM(S): Mus musculus

PROVIDER: GSE173144 | GEO | 2021/06/01

REPOSITORIES: GEO

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Project description:Innate immune responses are important in combating various microbes during the early phases of infection. Natural killer (NK) cells are innate lymphocytes that, unlike T and B lymphocytes, do not express antigen receptors but rapidly exhibit cytotoxic activities against virus infected cells and produce various cytokines1,2. We report here a new type of innate lymphocyte present in a novel lymphoid structure associated with adipose tissues in the peritoneal cavity. These cells do not express lineage (Lin) markers but express c-Kit, Sca-1, IL-7R and IL-33R. Similar lymphoid clusters were found in both human and mouse mesentery and we term this tissue â??FALCâ?? for fat-associated lymphoid cluster. FALC Lin-c-Kit+Sca-1+ cells are distinct from lymphoid progenitors3 and lymphoid tissue inducer (LTi) cells4. These cells proliferate in response to IL-2 and produce large amounts of Th2 cytokines such as IL-5, IL-6 and IL-13. IL-5 and IL-6 regulate B cell antibody production and self-renewal of B1 cells5-7. Indeed, FALC Lin-c-Kit+Sca-1+ cells support the self-renewal of B1 cells and enhance IgA production. IL-5 and IL-13 mediate allergic inflammation and protection against helminth infection8,9. Upon helminth infection and in response to IL-33, FALC Lin-c-Kit+Sca-1+ cells produce large amounts of IL-13, which leads to goblet cell hyperplasia, a critical step for helminth expulsion. In mice devoid of FALC Lin-c-Kit+Sca-1+ cells such goblet cell hyperplasia was not induced. Thus, FALC Lin-c-Kit+Sca-1+ cells are Th2-type innate lymphocytes and we propose that these cells be called â??natural helper cellsâ??. Experiment Overall Design: Natural helper cells (Lin- c-kit+ Sca-1+) were isolated from mesentery of C57BL/6 for RNA extraction and hybridization on Affymetrix microarrays. For the control of this experiment, we use double negative cells (DN2) from thymus of C57BL/6 or lymphoid tissue inducer cells (LTi). Thymic DN2 cells were prepared from adult thymocytes. Thymocytes were stained with magnetic beads conjugated with anti-CD4 and anti-CD8Î± mAbs and CD4-CD8- double negative (DN) cells were negatively sorted by AutoMACS. DN cells were further stained with anti-CD25 and anti-CD44 mAbs and CD25+CD44+ cells were sorted as DN2 cells on a FACSAria.Thy-1+CD4- LTi cells were prepared from fetal liver cells as described previously. c-Kit+Î±4Î²7+IL-7RÎ±+ fetal liver cells from day 13 embryos were cultured on TSt4 cells for 17 days.

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Spatial Distribution of LTi-like Cells in Intestinal Mucosa Regulates Type 3 Innate Immunity

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