title: Lymphotoxin controls the IL-22 protection pathway in gut innate lymphoid cells during mucosal pathogen challenge.
abstract: Innate lymphoid cells (ILCs) have emerged as important players, regulating the balance between protective immunity and immunopathology at mucosal surfaces. However, mechanisms that regulate ILCs' effector functions during mucosal pathogenic challenge are poorly defined. Using mice infected with the natural mouse enteric pathogen Citrobacter rodentium, we demonstrate that lymphotoxin (LT) is essential for IL-22 production by intestinal ILCs. Blocking of LTβR signaling dramatically reduced intestinal IL-22 production after C. rodentium infection. Conversely, stimulating LTβR signaling induced an IL-22 protection pathway in LT-deficient mice. Furthermore, exogenous IL-22 expression rescued LTβR-deficient mice. IL-22-producing ILCs were predominantly located in lymphoid follicles in the colon and interacted closely with dendritic cells (DCs). We find that an LT-driven positive feedback loop controls IL-22 production by RORγt(+) ILCs via LTβR signaling in DCs. Taken together, our data show that LTβR signaling in gut lymphoid follicles regulates IL-22 production by ILCs in response to mucosal pathogen challenge.
authors.affiliation: Department of Pathology, The University of Chicago, Chicago, IL 60637, USA. atumanov@trudeauinstitute.org
authors.forename: Alexei V
authors.initials: AV
authors.lastname: Tumanov
authors.forename: Ekaterina P
authors.initials: EP
authors.lastname: Koroleva
authors.forename: Xiaohuan
authors.initials: X
authors.lastname: Guo
authors.forename: Yugang
authors.initials: Y
authors.lastname: Wang
authors.forename: Andrei
authors.initials: A
authors.lastname: Kruglov
authors.forename: Sergei
authors.initials: S
authors.lastname: Nedospasov
authors.forename: Yang-Xin
authors.initials: YX
authors.lastname: Fu
mesh_terms: D000818:Animals; D044082:Citrobacter rodentium / Q000472:pathogenicity*; D003106:Colon / Q000378:metabolism; D016207:Cytokines / Q000378:metabolism; D003713:Dendritic Cells / Q000276:immunology / Q000378:metabolism; D004756:Enterobacteriaceae Infections / Q000276:immunology / Q000378:metabolism; D007113:Immunity, Innate; D007378:Interleukins / Q000276:immunology / Q000378:metabolism*; D007413:Intestinal Mucosa / Q000276:immunology / Q000382:microbiology*; D008214:Lymphocytes / Q000276:immunology* / Q000378:metabolism; D053259:Lymphotoxin beta Receptor / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008233:Lymphotoxin-alpha / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D000097043:Interleukin-22
chemical_list: D016207:Cytokines; D007378:Interleukins; D053259:Lymphotoxin beta Receptor; D008233:Lymphotoxin-alpha; D057132:Nuclear Receptor Subfamily 1, Group F, Member 3; D000097043:Interleukin-22; C539901:Rorc protein, mouse