title: Lnk/Sh2b3 controls the production and function of dendritic cells and regulates the induction of IFN-γ-producing T cells.
abstract: Dendritic cells (DCs) are proficient APCs that play crucial roles in the immune responses to various Ags and pathogens and polarize Th cell immune responses. Lnk/SH2B adaptor protein 3 (Sh2b3) is an intracellular adaptor protein that regulates B lymphopoiesis, megakaryopoiesis, and expansion of hematopoietic stem cells by constraining cytokine signals. Recent genome-wide association studies have revealed a link between polymorphism in this adaptor protein and autoimmune diseases, including type 1 diabetes and celiac disease. We found that Lnk/Sh2b3 was also expressed in DCs and investigated its role in the production and function of DC lineage cells. In Lnk(-/-) mice, DC numbers were increased in the spleen and lymph nodes, and growth responses of bone marrow-derived DCs to GM-CSF were augmented. Mature DCs from Lnk(-/-) mice were hypersensitive and showed enhanced responses to IL-15 and GM-CSF. Compared to normal DCs, Lnk(-/-) DCs had enhanced abilities to support the differentiation of IFN-γ-producing Th1 cells from naive CD4(+) T cells. This was due to their elevated expression of IL-12Rβ1 and increased production of IFN-γ. Lnk(-/-) DCs supported the appearance of IFN-γ-producing T cells even under conditions in which normal DCs supported induction of regulatory T cells. These results indicated that Lnk/Sh2b3 plays a regulatory role in the expansion of DCs and might influence inflammatory immune responses in peripheral lymphoid tissues.
authors.affiliation: Department of Immune Regulation, Research Institute, National Center for Global Health and Medicine, Chiba 272-8516, Japan;
authors.forename: Taizo
authors.initials: T
authors.lastname: Mori
authors.affiliation: Department of Immune Regulation, Research Institute, National Center for Global Health and Medicine, Chiba 272-8516, Japan; Department of Allergy and Rheumatology, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan;
authors.forename: Yukiko
authors.initials: Y
authors.lastname: Iwasaki
authors.affiliation: Department of Immune Regulation, Research Institute, National Center for Global Health and Medicine, Chiba 272-8516, Japan;
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Seki
authors.affiliation: Department of Immune Regulation, Research Institute, National Center for Global Health and Medicine, Chiba 272-8516, Japan;
authors.forename: Masanori
authors.initials: M
authors.lastname: Iseki
authors.affiliation: Department of Immune Regulation, Research Institute, National Center for Global Health and Medicine, Chiba 272-8516, Japan;
authors.forename: Hiroko
authors.initials: H
authors.lastname: Katayama
authors.affiliation: Department of Allergy and Rheumatology, Graduate School of Medicine, University of Tokyo, Tokyo 113-8655, Japan;
authors.forename: Kazuhiko
authors.initials: K
authors.lastname: Yamamoto
authors.affiliation: Department of Immunobiology and Pharmacological Genetics, Graduate School of Medicine and Pharmaceutical Science for Research, University of Toyama, Toyama 930-0194, Japan; and Prefectural Institute for Pharmaceutical Research, Toyama 939-0363, Japan.
authors.forename: Kiyoshi
authors.initials: K
authors.lastname: Takatsu
authors.affiliation: Department of Immune Regulation, Research Institute, National Center for Global Health and Medicine, Chiba 272-8516, Japan; lbstakaki@hospk.ncgm.go.jp.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Takaki
mesh_terms: D048868:Adaptor Proteins, Signal Transducing; D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D001854:Bone Marrow Cells / Q000166:cytology; D002446:Celiac Disease / Q000276:immunology; D002454:Cell Differentiation / Q000276:immunology; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology*; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology; D055106:Genome-Wide Association Study; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000494:pharmacology; D006412:Hematopoietic Stem Cells / Q000276:immunology; D007249:Inflammation / Q000276:immunology; D007371:Interferon-gamma / Q000096:biosynthesis*; D018664:Interleukin-12 / Q000494:pharmacology; D019409:Interleukin-15 / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins / Q000096:biosynthesis / Q000235:genetics*; D008198:Lymph Nodes / Q000166:cytology; D008213:Lymphocyte Activation / Q000276:immunology; D038041:Lymphopoiesis / Q000276:immunology*; D008565:Membrane Proteins / Q000494:pharmacology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D020641:Polymorphism, Single Nucleotide; D053707:Receptors, Interleukin-12 / Q000096:biosynthesis; D013154:Spleen / Q000166:cytology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology*; D034061:Thrombopoiesis / Q000276:immunology
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000276:Adjuvants, Immunologic; C508440:Il12rb1 protein, mouse; D019409:Interleukin-15; D047908:Intracellular Signaling Peptides and Proteins; C490777:Lnk protein, mouse; D008565:Membrane Proteins; D053707:Receptors, Interleukin-12; C084881:flt3 ligand protein; D018664:Interleukin-12; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor