Lnk/Sh2b3 controls the production and function of dendritic cells and regulates the induction of IFN-γ-producing T cells

J Immunol. 2014 Aug 15;193(4):1728-36. doi: 10.4049/jimmunol.1303243. Epub 2014 Jul 14.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Adjuvants, Immunologic / pharmacology
  • Animals
  • Bone Marrow Cells / cytology
  • Celiac Disease / immunology
  • Cell Differentiation / immunology
  • Cells, Cultured
  • Dendritic Cells / immunology*
  • Diabetes Mellitus, Type 1 / immunology
  • Genome-Wide Association Study
  • Granulocyte-Macrophage Colony-Stimulating Factor / pharmacology
  • Hematopoietic Stem Cells / immunology
  • Inflammation / immunology
  • Interferon-gamma / biosynthesis*
  • Interleukin-12 / pharmacology
  • Interleukin-15 / pharmacology
  • Intracellular Signaling Peptides and Proteins / biosynthesis
  • Intracellular Signaling Peptides and Proteins / genetics*
  • Lymph Nodes / cytology
  • Lymphocyte Activation / immunology
  • Lymphopoiesis / immunology*
  • Membrane Proteins / pharmacology
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Polymorphism, Single Nucleotide
  • Receptors, Interleukin-12 / biosynthesis
  • Spleen / cytology
  • T-Lymphocytes, Regulatory / immunology
  • Th1 Cells / immunology*
  • Thrombopoiesis / immunology

Substances

  • Adaptor Proteins, Signal Transducing
  • Adjuvants, Immunologic
  • Il12rb1 protein, mouse
  • Interleukin-15
  • Intracellular Signaling Peptides and Proteins
  • Lnk protein, mouse
  • Membrane Proteins
  • Receptors, Interleukin-12
  • flt3 ligand protein
  • Interleukin-12
  • Interferon-gamma
  • Granulocyte-Macrophage Colony-Stimulating Factor