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T cell CD3? deficiency enables multiorgan tissue inflammation.

ABSTRACT: Although a population of T cells with CD3? chain deficiency has been found in patients with systemic lupus erythematosus, rheumatoid arthritis, cancer, and infectious disease, the role of CD3? chain in the disease pathogenesis remains unknown. To understand the contribution of CD3? deficiency to the expression of organ injury, we have performed the following studies. We used CD3?-deficient mice to investigate the role of CD3? in the pathogenesis of organ tissue inflammation. We found that the CD3?(-/-) mice can spontaneously develop significant organ inflammation that can be accelerated following the administration of polyinosinic:polycytidylic acid or allogeneic cells (graft versus host). T cells from CD3?(-/-) mice display increased expression of the adhesion molecules CD44 and CCR2 and produce increased amounts of IFN-? blockade, which mitigates tissue inflammation. Our results demonstrate that CD3? deficiency bestows T cells with the ability to infiltrate various tissues and instigate inflammation. Decreased CD3? expression noted in T cells from various diseases contributes independently to tissue inflammation and organ damage. Approaches to restore CD3? expression of the surface of T cells should be expected to mitigate tissue inflammation.

SUBMITTER: Deng GM

PROVIDER: S-EPMC4070291 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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T cell CD3ζ deficiency enables multiorgan tissue inflammation.

Deng Guo-Min GM Beltran Jessica J Chen Chen C Terhorst Cox C Tsokos George C GC

Journal of immunology (Baltimore, Md. : 1950) 20130826 7

Although a population of T cells with CD3ζ chain deficiency has been found in patients with systemic lupus erythematosus, rheumatoid arthritis, cancer, and infectious disease, the role of CD3ζ chain in the disease pathogenesis remains unknown. To understand the contribution of CD3ζ deficiency to the expression of organ injury, we have performed the following studies. We used CD3ζ-deficient mice to investigate the role of CD3ζ in the pathogenesis of organ tissue inflammation. We found that the CD ...[more]

PMID: 23980209

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Project description:Type 2 diabetes (T2DM) is a heterogeneous group of diseases that is progressive and involves multiple tissues. Goto-Kakizaki (GK) rats are a polygenic model with elevated blood glucose, peripheral insulin resistance, a non-obese phenotype, and exhibit many degenerative changes observed in human T2DM. As part of a systems analysis of disease progression in this animal model, this study characterized the contribution of adipose tissue to pathophysiology of the disease. We sacrificed subgroups of GK rats and appropriate controls at 4, 8, 12, 16 and 20 weeks of age and carried out a gene array analysis of white adipose tissue. We expanded our physiological analysis of the animals that accompanied our initial gene array study on the livers from these animals. The expanded analysis included adipose tissue weights, HbA1c, additional hormonal profiles, lipid profiles, differential blood cell counts, and food consumption. HbA1c progressively increased in the GK animals. Altered corticosterone, leptin, and adiponectin profiles were also documented in GK animals. Gene array analysis identified 412 genes that were differentially expressed in adipose tissue of GKs relative to controls. The GK animals exhibited an age-specific failure to accumulate body fat despite their relatively higher calorie consumption which was well supported by the altered expression of genes involved in adipogenesis and lipogenesis in the white adipose tissue of these animals, including Fasn, Acly, Kklf9, and Stat3. Systemic inflammation was reflected by chronically elevated white blood cell counts. Furthermore, chronic inflammation in adipose tissue was evident from the differential expression of genes involved in inflammatory responses and activation of natural immunity, including two interferon regulated genes, Ifit and Iipg, as well as MHC class II genes. This study demonstrates an age specific failure to accumulate adipose tissue in the GK rat and the presence of chronic inflammation in adipose tissue from these animals.

Project description:OBJECTIVES:High-fat diet (HFD) feeding in mice is characterized by accumulation of ?? T cells in adipose tissue. However, the contribution of ?? T cells to obesity-induced inflammation of skeletal muscle, a major organ of glucose uptake, is unknown. This study was undertaken to evaluate the effect of ?? T cells on insulin sensitivity and inflammatory state of skeletal muscle and adipose tissue in obesity. Furthermore, we investigated whether CD4+IFN?+ (TH1) cells are involved in skeletal muscle and adipose tissue metabolic dysfunction that accompanies obesity. METHODS:Mice lacking ?? T cells (T cell receptor beta chain-deficient [TCRb-/-] mice) were fed HFD for 12 weeks. Obesity-induced skeletal muscle and adipose tissue inflammation was assessed by flow cytometry and quantitative RT-PCR. To investigate the effect of TH1 cells on skeletal muscle and adipose tissue inflammation and metabolic functions, we injected 5×10(5) TH1 cells or PBS weekly over 12 weeks into HFD-fed TCRb-/- mice. We also cultured C2C12 myofibers and 3T3-L1 adipocytes with TH1-conditioned medium. RESULTS:We showed that similar to adipose tissue, skeletal muscle of obese mice have higher ?? T cell content, including TH1 cells. TCRb-/- mice were protected against obesity-induced hyperglycemia and insulin resistance. We also demonstrated suppressed macrophage infiltration and reduced inflammatory cytokine expression in skeletal muscle and adipose tissue of TCRb-/- mice on HFD compared to wild-type obese controls. Adoptive transfer of TH1 cells into HFD-fed TCRb-/- mice resulted in increased skeletal muscle and adipose tissue inflammation and impaired glucose metabolism. TH1 cells directly impaired functions of C2C12 myotubes and 3T3-L1 adipocytes in vitro. CONCLUSIONS:We conclude that reduced adipose tissue and skeletal muscle inflammation in obese TCRb-/- mice is partially attributable to the absence of TH1 cells. Our results suggest an important role of TH1 cells in regulating inflammation and insulin resistance in obesity.

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T cell CD3? deficiency enables multiorgan tissue inflammation.

Publications

T cell CD3ζ deficiency enables multiorgan tissue inflammation.

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