title: Defect in regulatory B-cell function and development of systemic autoimmunity in T-cell Ig mucin 1 (Tim-1) mucin domain-mutant mice.
abstract: 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.
authors: Center for Neurologic Disease, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA.
authors: Sheng
authors: S
authors: Xiao
authors: Craig R
authors: CR
authors: Brooks
authors: Chen
authors: C
authors: Zhu
authors: Chuan
authors: C
authors: Wu
authors: Johanna M
authors: JM
authors: Sweere
authors: Sonia
authors: S
authors: Petecka
authors: Ada
authors: A
authors: Yeste
authors: Francisco J
authors: FJ
authors: Quintana
authors: Takaharu
authors: T
authors: Ichimura
authors: Raymond A
authors: RA
authors: Sobel
authors: Joseph V
authors: JV
authors: Bonventre
authors: Vijay K
authors: VK
authors: Kuchroo
mesh_terms: D000818:Animals; D001323:Autoantibodies / Q000097:blood; D015551:Autoimmunity / Q000235:genetics* / Q000276:immunology; D060151:B-Lymphocytes, Regulatory / Q000276:immunology* / Q000378:metabolism; D015153:Blotting, Western; D003433:Crosses, Genetic; D017931:DNA Primers; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D000072596:Hepatitis A Virus Cellular Receptor 1; D007371:Interferon-gamma / Q000097:blood; D016753:Interleukin-10 / Q000378:metabolism; D008565:Membrane Proteins / Q000235:genetics* / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009077:Mucins / Q000235:genetics; D016296:Mutagenesis; D017434:Protein Structure, Tertiary / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013601:T-Lymphocytes / Q000276:immunology* / Q000378:metabolism
chemical_list: D001323:Autoantibodies; D017931:DNA Primers; C442240:Havcr1 protein, mouse; D000072596:Hepatitis A Virus Cellular Receptor 1; D008565:Membrane Proteins; D009077:Mucins; D016753:Interleukin-10; D007371:Interferon-gamma