title: Lnk prevents inflammatory CD8⁺ T-cell proliferation and contributes to intestinal homeostasis.
abstract: The intracellular adaptor Lnk (also known as SH2B3) regulates cytokine signals that control lymphohematopoiesis, and Lnk(-/-) mice have expanded B-cell, megakaryocyte, and hematopoietic stem-cell populations. Moreover, mutations in the LNK gene are found in patients with myeloproliferative disease, whereas LNK polymorphisms have recently been associated with inflammatory and autoimmune diseases, including celiac disease. Here, we describe a previously unrecognized function of Lnk in the control of inflammatory CD8(+) T-cell proliferation and in intestinal homeostasis. Mature T cells from newly generated Lnk-Venus reporter mice had low but substantial expression of Lnk, whereas Lnk expression was downregulated during homeostatic T-cell proliferation under lymphopenic conditions. The numbers of CD44(hi) IFN-γ(+) CD8(+) effector or memory T cells were found to be increased in Lnk(-/-) mice, which also exhibited shortening of villi in the small intestine. Lnk(-/-) CD8(+) T cells survived longer in response to stimulation with IL-15 and proliferated even in nonlymphopenic hosts. Transfer of Lnk(-/-) CD8(+) T cells together with WT CD4(+) T cells into Rag2-deficient mice recapitulated a sign of villous abnormality. Our results reveal a link between Lnk and immune cell-mediated intestinal tissue destruction.
authors.affiliation: Department of Immune Regulation, Research Institute, National Center for Global Health and Medicine, Ichikawa, Chiba, Japan.
authors.forename: Hiroko
authors.initials: H
authors.lastname: Katayama
authors.forename: Taizo
authors.initials: T
authors.lastname: Mori
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Seki
authors.forename: Masaki
authors.initials: M
authors.lastname: Anraku
authors.forename: Masanori
authors.initials: M
authors.lastname: Iseki
authors.forename: Masashi
authors.initials: M
authors.lastname: Ikutani
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Iwasaki
authors.forename: Nobuaki
authors.initials: N
authors.lastname: Yoshida
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Takatsu
authors.forename: Satoshi
authors.initials: S
authors.lastname: Takaki
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D049109:Cell Proliferation; D004268:DNA-Binding Proteins / Q000235:genetics / Q000276:immunology; D006706:Homeostasis / Q000235:genetics / Q000276:immunology*; D018960:Hyaluronan Receptors / Q000235:genetics / Q000276:immunology; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000473:pathology; D007422:Intestines / Q000276:immunology* / Q000473:pathology; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000276:immunology*; D008565:Membrane Proteins; D051379:Mice; D018345:Mice, Knockout; D011110:Polymorphism, Genetic / Q000276:immunology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; C476399:Cd44 protein, mouse; D004268:DNA-Binding Proteins; D018960:Hyaluronan Receptors; D047908:Intracellular Signaling Peptides and Proteins; C490777:Lnk protein, mouse; D008565:Membrane Proteins; C499308:Rag2 protein, mouse
keywords: Autoimmune disease; Cytokine signaling; Disease-associated gene; IL-15