title: Interleukin-22 protects intestinal stem cells from immune-mediated tissue damage and regulates sensitivity to graft versus host disease.
abstract: Little is known about the maintenance of intestinal stem cells (ISCs) and progenitors during immune-mediated tissue damage or about the susceptibility of transplant recipients to tissue damage mediated by the donor immune system during graft versus host disease (GVHD). We demonstrate here that deficiency of recipient-derived IL-22 increased acute GVHD tissue damage and mortality, that ISCs were eliminated during GVHD, and that ISCs as well as their downstream progenitors expressed the IL-22 receptor. Intestinal IL-22 was produced after bone marrow transplant by IL-23-responsive innate lymphoid cells (ILCs) from the transplant recipients, and intestinal IL-22 increased in response to pretransplant conditioning. However, ILC frequency and IL-22 amounts were decreased by GVHD. Recipient IL-22 deficiency led to increased crypt apoptosis, depletion of ISCs, and loss of epithelial integrity. Our findings reveal IL-22 as a critical regulator of tissue sensitivity to GVHD and a protective factor for ISCs during inflammatory intestinal damage.
authors.affiliation: Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA. hanasha@mskcc.org
authors.forename: Alan M
authors.initials: AM
authors.lastname: Hanash
authors.forename: Jarrod A
authors.initials: JA
authors.lastname: Dudakov
authors.forename: Guoqiang
authors.initials: G
authors.lastname: Hua
authors.forename: Margaret H
authors.initials: MH
authors.lastname: O'Connor
authors.forename: Lauren F
authors.initials: LF
authors.lastname: Young
authors.forename: Natalie V
authors.initials: NV
authors.lastname: Singer
authors.forename: Mallory L
authors.initials: ML
authors.lastname: West
authors.forename: Robert R
authors.initials: RR
authors.lastname: Jenq
authors.forename: Amanda M
authors.initials: AM
authors.lastname: Holland
authors.forename: Lucy W
authors.initials: LW
authors.lastname: Kappel
authors.forename: Arnab
authors.initials: A
authors.lastname: Ghosh
authors.forename: Jennifer J
authors.initials: JJ
authors.lastname: Tsai
authors.forename: Uttam K
authors.initials: UK
authors.lastname: Rao
authors.forename: Nury L
authors.initials: NL
authors.lastname: Yim
authors.forename: Odette M
authors.initials: OM
authors.lastname: Smith
authors.forename: Enrico
authors.initials: E
authors.lastname: Velardi
authors.forename: Elena B
authors.initials: EB
authors.lastname: Hawryluk
authors.forename: George F
authors.initials: GF
authors.lastname: Murphy
authors.forename: Chen
authors.initials: C
authors.lastname: Liu
authors.forename: Lynette A
authors.initials: LA
authors.lastname: Fouser
authors.forename: Richard
authors.initials: R
authors.lastname: Kolesnick
authors.forename: Bruce R
authors.initials: BR
authors.lastname: Blazar
authors.forename: Marcel R M
authors.initials: MR
authors.lastname: van den Brink
mesh_terms: D000818:Animals; D016026:Bone Marrow Transplantation / Q000009:adverse effects / Q000276:immunology*; D004195:Disease Models, Animal; D005434:Flow Cytometry; D006086:Graft vs Host Disease / Q000276:immunology* / Q000401:mortality; D007150:Immunohistochemistry; D053759:Interleukin-23 / Q000378:metabolism; D007378:Interleukins / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D007421:Intestine, Small / Q000166:cytology / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018123:Receptors, Interleukin / Q000378:metabolism; D013234:Stem Cells / Q000378:metabolism*; D000097043:Interleukin-22
chemical_list: D053759:Interleukin-23; D007378:Interleukins; D018123:Receptors, Interleukin; D000097043:Interleukin-22; C415369:interleukin-22 receptor