Identification of Tapr (an airway hyperreactivity regulatory locus) and the linked Tim gene family

McIntire, Jennifer J.; Umetsu, Sarah E.; Akbari, Omid; Potter, Michael; Kuchroo, Vijay K.; Barsh, Gregory S.; Freeman, Gordon J.; Umetsu, Dale T.; DeKruyff, Rosemarie H.

doi:10.1038/ni739

Cited by 452 publications

(444 citation statements)

References 57 publications

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“…14 Tapr, a locus that regulates mouse airway hyperreactivity and Th2 differentiation, has also been identified in a similar region using chromosome 11 congenic mice, which were derived from BALB/c and DBA/2. 30 These findings are not inconsistent with our own. It is possible that the genetic contributions from chromosome 11 loci are strain specific and did not contribute sufficient phenotype dosage, relative to Tsi1-3, to become apparent in our experimental cross.…”

Section: Discussionsupporting

confidence: 65%

Linkage analysis of the genetic determinants of T-cell IL-4 secretion, and identification of Flj20274 as a putative candidate gene

Choi

Rose

et al. 2005

Genes Immun

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Section: Discussionsupporting

confidence: 65%

Linkage analysis of the genetic determinants of T-cell IL-4 secretion, and identification of Flj20274 as a putative candidate gene

Choi

Rose

et al. 2005

Genes Immun

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“…However, this amino acid change (Q291L) is not at a critical site for carbohydrate recognition [17]. It has been reported that seven amino acid variations exist between the extracellular Ig domain of TIM-3 in different mouse strains [18] and that these variations may be involved in differential regulation of the Th1 response. BALB/c mice, which tend to develop Th2-biased immune responses with enhanced airway hyperreactivity, have different TIM-3 alleles than do C57BL/6 and DBA/2 mice that have Th1-prone immunity.…”

Section: Resultsmentioning

confidence: 99%

Attenuation of Th1 response through galectin‐9 and T‐cell Ig mucin 3 interaction inhibits autoimmune diabetes in NOD mice

2009

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Galectin-9 (gal-9), widely expressed in many tissues, regulates Th1 cells and induces their apoptosis through its receptor, T-cell Ig mucin 3, which is mainly expressed on terminally differentiated Th1 cells. Type 1 diabetes is a Th1-dominant autoimmune disease that specifically destroys insulin-producing b cells. To suppress the Th1 immune response in the development of autoimmune diabetes, we overexpressed gal-9 in NOD mice by injection of a plasmid encoding gal-9. Mice treated with gal-9 plasmid were significantly protected from diabetes and showed less severe insulitis compared with controls. Flow cytometric analyses in NOD-T1/2 double transgenic mice showed that Th1-cell population in spleen, pancreatic lymph node and pancreas was markedly decreased in gal-9 plasmidtreated mice, indicating a negative regulatory role of gal-9 in the development of pathogenic Th1 cells. Splenocytes from gal-9 plasmid-treated mice were less responsive to mitogenic stimulation than splenocytes from the control group. However, adoptive transfer of splenocytes from gal-9-treated or control mice caused diabetes in NOD/SCID recipients with similar kinetics, suggesting that gal-9 treatment does not induce active tolerance in NOD mice. We conclude that gal-9 may downregulate Th1 immune response in NOD mice and could be used as a therapeutic target in autoimmune diabetes.Key words: Galectin-9 . Th1 . T-cell Ig mucin 3 . Type 1 diabetes IntroductionWhen CD4 1 Th cells interact with class II MHC-peptide complex and costimulatory molecules on APC, they differentiate into several effector subsets. There are two major Th subsets that have unique patterns of cytokine secretion and different functional properties. Th1 cells produce cytokines such as IFN-g, IL-2, TNF-a and lymphotoxin that are commonly associated with cellmediated immune responses against intracellular pathogens, delayed-type hypersensitivity and induction of organ-specific autoimmune diseases. Th2 cells produce cytokines such as IL-4, IL-5, IL-10 and IL-13 that are crucial for controlling extracellular helminth infections and promoting atopic and allergic diseases [1,2].Type 1 diabetes (T1D) is a T-cell-mediated autoimmune disease that selectively destroys the insulin-producing b cells in the pancreas. NOD mice spontaneously develop autoimmune diabetes with immunopathological features resembling those of human disease and can be used as an animal model to study the pathogenesis of T1D. Previous studies have demonstrated that transfer of NOD CD4 1 T cells to immunodeficient NOD/SCID mice can induce diabetes in those recipients, indicating that CD4 1 T cells play an important role in the pathogenesis of diabetes [3,4] [12]. Previous approaches using TIM-3-Ig fusion protein to interrupt the interactions between TIM-3 and its ligand in vivo resulted in hyperproliferation of Th1 cells and release of Th1-related cytokines [13]. TIM-3 ligand was subsequently identified as galectin-9 (gal-9) [14], a b-galactoside binding lectin that belongs to a growing family of animal lectins, the...

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“…30 The TIM gene family includes three members (Tim-1, Tim-3 and Tim-4) in humans and eight members (Tim-1 to Tim-8) in mice. 31 Due to its unique structure, the TIM gene family is thought to participate in the regulation of immunological processes.…”

Section: Discussionmentioning

confidence: 99%

Increased expression of human T-cell immunoglobulin- and mucin-domain-containing molecule-4 in peripheral blood mononuclear cells from patients with system lupus erythematosus

Zhao

Wang³

et al. 2010

Cell Mol Immunol

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Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease. Innate and adaptive immunity cooperatively contribute to the development of SLE. Antigen-presenting cells (APCs) have been suggested to link innate and adaptive immunity. T-cell immunoglobulin-and mucin-domain-containing molecule-4 (Tim-4; also known as Timd4), expressed primarily on the surface of APCs, is a member of the TIM family, a recently described group of molecules that have received much attention as potential regulators of the immune system. In this study, we used quantitative real-time reverse transcription-polymerase chain reaction to examine the mRNA expression of Tim-4 in peripheral blood mononuclear cells (PBMCs) from SLE patients and further analyzed the correlation between the expression of Tim-4 and Tim-1 (a potential ligand for Tim-4) in PBMCs and serum tumor necrosis factor (TNF)-a levels. The results showed that Tim-4 mRNA expression in PBMCs was significantly higher in SLE patients than in healthy controls, especially those patients in the active phase of disease. Moreover, Tim-4 mRNA levels were closely correlated with Tim-1 mRNA levels in PBMCs and with serum TNF-a levels in SLE patients but not in the control group. Taken together, these results demonstrate that Tim-4 may be involved in the pathogenesis of SLE.

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Identification of Tapr (an airway hyperreactivity regulatory locus) and the linked Tim gene family

Cited by 452 publications

References 57 publications

Linkage analysis of the genetic determinants of T-cell IL-4 secretion, and identification of Flj20274 as a putative candidate gene

Linkage analysis of the genetic determinants of T-cell IL-4 secretion, and identification of Flj20274 as a putative candidate gene

Attenuation of Th1 response through galectin‐9 and T‐cell Ig mucin 3 interaction inhibits autoimmune diabetes in NOD mice

Increased expression of human T-cell immunoglobulin- and mucin-domain-containing molecule-4 in peripheral blood mononuclear cells from patients with system lupus erythematosus

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