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Defect in regulatory B-cell function and development of systemic autoimmunity in T-cell Ig mucin 1 (Tim-1) mucin domain-mutant mice.

Tim-1, a type I transmembrane glycoprotein, consists of an IgV domain and a mucin domain. The IgV domain is essential for binding Tim-1 to its ligands, but little is known about the role of the mucin domain, even though genetic association of TIM-1 with atopy/asthma has been linked to the length of mucin domain. We generated a Tim-1-mutant mouse (Tim-1(Δmucin)) in which the mucin domain was deleted genetically. The mutant mice showed a profound defect in IL-10 production from regulatory B cells (Bregs). Associated with the loss of IL-10 production in B cells, older Tim-1(Δmucin) mice developed spontaneous autoimmunity associated with hyperactive T cells, with increased production of IFN-γ and elevated serum levels of Ig and autoantibodies. However, Tim-1(Δmucin) mice did not develop frank systemic autoimmune disease unless they were crossed onto the Fas-mutant lpr mice on a C57BL/6 background. Tim-1(Δmucin)lpr mice developed accelerated and fulminant systemic autoimmunity with accumulation of abnormal double-negative T cells and autoantibodies to a number of lupus-associated autoantigens. Thus, Tim-1 plays a critical role in maintaining suppressive Breg function, and our data also demonstrate an unexpected role of the Tim-1 mucin domain in regulating Breg function and maintaining self-tolerance.

Pubmed ID: 22773818

Authors

  • Xiao S
  • Brooks CR
  • Zhu C
  • Wu C
  • Sweere JM
  • Petecka S
  • Yeste A
  • Quintana FJ
  • Ichimura T
  • Sobel RA
  • Bonventre JV
  • Kuchroo VK

Journal

Proceedings of the National Academy of Sciences of the United States of America

Publication Data

July 24, 2012

Associated Grants

  • Agency: NIDDK NIH HHS, Id: K01 DK090105
  • Agency: NIDDK NIH HHS, Id: K01DK090105
  • Agency: NIAID NIH HHS, Id: P01AI039671
  • Agency: NIAID NIH HHS, Id: P01AI073748
  • Agency: NINDS NIH HHS, Id: P01NS038037
  • Agency: NIDDK NIH HHS, Id: R01 DK072381
  • Agency: NINDS NIH HHS, Id: R01 NS030843
  • Agency: NIAID NIH HHS, Id: R01AI044880
  • Agency: NIDDK NIH HHS, Id: R01DK072381
  • Agency: NIDDK NIH HHS, Id: R01DK39773
  • Agency: NINDS NIH HHS, Id: R01NS035685
  • Agency: NINDS NIH HHS, Id: R01NS045937
  • Agency: NIDDK NIH HHS, Id: R37 DK039773
  • Agency: NINDS NIH HHS, Id: R37NS030843

Mesh Terms

  • Animals
  • Autoantibodies
  • Autoimmunity
  • B-Lymphocytes, Regulatory
  • Blotting, Western
  • Crosses, Genetic
  • DNA Primers
  • Enzyme-Linked Immunosorbent Assay
  • Flow Cytometry
  • Interferon-gamma
  • Interleukin-10
  • Membrane Proteins
  • Mice
  • Mice, Inbred C57BL
  • Mice, Mutant Strains
  • Mucins
  • Mutagenesis
  • Protein Structure, Tertiary
  • Reverse Transcriptase Polymerase Chain Reaction
  • T-Lymphocytes