Craig brooks
Faculty Member
Last active: 3/14/2019

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

Xiao S, Brooks CR, Zhu C, Wu C, Sweere JM, Petecka S, Yeste A, Quintana FJ, Ichimura T, Sobel RA, Bonventre JV, Kuchroo VK
Proc Natl Acad Sci U S A. 2012 109 (30): 12105-10

PMID: 22773818 · PMCID: PMC3409739 · DOI:10.1073/pnas.1120914109

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.

MeSH Terms (21)

Animals Autoantibodies Autoimmunity B-Lymphocytes, Regulatory Blotting, Western Crosses, Genetic DNA Primers Enzyme-Linked Immunosorbent Assay Flow Cytometry Hepatitis A Virus Cellular Receptor 1 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

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