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.

KIM-1–mediated phagocytosis reduces acute injury to the kidney

“…Δmucin mice were found to have similar mRNA expression levels of the closest of the TIM genes in the KIM-1 locus (17). We confirmed that other TIMs, TIM-3 and TIM-4, are not differentially regulated in KIM-1…”

“…Consistent with the absence of a significant effect of KIM-1 Δmucin BM-derived cells, it has been reported that there were very few differences found in the activity of T lymphocytes between WT and KIM-1 Δmucin mice of the same age used in this study (17). There was slightly increased IFN-γ production after activation with either plate-bound anti-CD3/CD28 or CD11c + DCs in the presence of soluble anti-CD3 (ref.…”

“…There was slightly increased IFN-γ production after activation with either plate-bound anti-CD3/CD28 or CD11c + DCs in the presence of soluble anti-CD3 (ref. 17 and data not shown).…”

“…A KIM-1-mutant mouse was created by replacing exon 3 of the KIM-1 gene with a PGK promoter-driven neomycin-resistance cassette on a C57BL/6 genetic background. This mutant mouse generated KIM-1 proteins with the loss of the mucin domain, encoded by exon 3 (KIM-1 Δmucin ) (17). KIM-1…”

Insulin-like Growth Factor-2 Enhances Functions of Antigen (Ag)-specific Regulatory B Cells

“…3P), which were in parallel to the frequency of IL-10 ϩ OVAsBCs in Fig. 3 Based on published data that IL-10-expressing B cells also express other cytokines (21,22), we further analyzed the phenotypes of IL-10 ϩ OVAsBCs. Positive staining of CD5, CD38, CD1d, TIM1, CD23, and CD27 was observed in 56 -78% of OVAsBCs.…”