After activation CD4+ helper T cells differentiate into T-helper (Th) 1 or Th2 effector cells. These two subsets are characterized by their distinct cytokine expression pattern and the immune function they mediate. Over the past years, a number of factors have been identified to affect helper T cell lineage determination, including antigen receptor, coreceptors and, most importantly, cytokine environment. In this review, we also summarize recent advancement in understanding of transcriptional and signaling regulation of the differentiation process. This knowledge will become important in the future to develop means in treating immune disorders.

BALB/c mice immunized with human cartilage proteoglycan (PG) develop arthritis accompanied by the production of autoantibodies to mouse cartilage PG. To determine whether the autoantibody isotype contributes to the onset and severity of arthritis, PG-specific serum IgG1 (Th2, IL-4-cytokine-supporting) and IgG2a (Th1, IFN-γ-controlling) concentrations were monitored during immunization with PG in IL-4-deficient and IFN-γ-deficient mice. Paradoxically, despite elevated IFN-γ, the PG-specific IgG1 isotype was significantly higher than the PG-specific IgG2a response, and the PG-specific IgG1 isotype was independent of IL-4. In contrast, the serum concentration of PG-specific IgG2a isotype was six times higher in IL-4-deficient mice than in wild-type controls. Moreover, the high concentration of PG-specific IgG2a isotype in IL-4-deficient mice corresponded to an increased severity of arthritis. The concentration of PG-specific IgG2a isotype was lower in IFN-γ-deficient mice than in wild-type mice, and the incidence and severity of arthritis also were significantly lower. Concentrations of PG-specific IgG2a isotype autoantibody correlated with the onset and severity of arthritis, suggesting a pathological role of this isotype, probably locally in the joint.

Background Tetracycline-regulated systems have been used to control the expression of heterologous genes in such diverse organisms as yeast, plants, flies and mice. Adaptation of this prokaryotic regulatory system avoids many of the problems inherent in other inducible systems. There have, however, been many reports of difficulties in establishing functioning stable cell lines due to the cytotoxic effects of expressing high levels of the tetracycline transactivator, tTA, from a strong viral promoter. Results Here we report the successful incorporation of tetracycline-mediated gene expression in a mouse mammary epithelial cell line, HC11, in which conventional approaches failed. We generated retroviruses in which tTA expression was controlled by one of three promoters: a synthetic tetracycline responsive promoter (TRE), the elongation factor 1-alpha promoter (EF1α) or the phosphoglycerate kinase-1 promoter (PGK), and compared the resulting cell lines to one generated using a cytomegalovirus immediate early gene promoter (CMV). In contrast to cells produced using the CMV and PGK promoters, those produced using the EF1α and TRE promoters expressed high levels of β-galactosidase in a tetracycline-dependent manner. Conclusions These novel retroviral vectors performed better than the commercially available system and may have a more general utility in similarly recalcitrant cell lines.

Transcriptional profiling of human lymphoblastoid TK6 cells comparing mock irradiaed cells resuspended in fresh untreated RPMI 1640 medium with cells resuspended in medium activated by exposure to 2.5 Gy HZE (1 GeV/amu iron ions accelerated at the NASA Space Research Laboratory (NSRL) of Brookhaven National Laboratory). Two-condition experiment, mock irradiated vs. cells exposed to activated medium. 3 biological replicates were independently grown and harvested during three different runs at the NSRL. One replicate per array.

The transcription factor NF-κB has been well recognized as a pivotal regulator of inflammation in rheumatoid arthritis (RA), but recent developments revealed a broad involvement of NF-κB in other aspects of RA pathology, including development of T helper 1 responses, activation, abnormal apoptosis and proliferation of RA fibroblast-like synovial cells, and differentiation and activation of bone resorbing activity of osteoclasts. In agreement with this, studies in animal models of RA have demonstrated the high therapeutic efficacy of specific inhibitors of NF-κB pathway, indicating the feasibility of anti-NF-κB therapy for human disease.

Recent studies have described the spontaneous development of arthritis or vasculitis in IL-1 receptor antagonist (IL-1Ra) knockout mice bred on specific and different genetic backgrounds. The levels of both secreted and intracellular isoforms of IL-1Ra produced in the rheumatoid joint or in the arterial wall may not be adequate to effectively inhibit the excess amounts of locally produced IL-1. Thus, an imbalance between IL-1 and IL-1Ra may predispose to local inflammatory disease in particular tissues in the presence of other as yet unknown genetically influenced factors.

The dataset shows the results of the Running Fisher test between the TGx-DDI biomarker and each of the qPCR-generated gene lists from chemical treatments in TK6 cells. The results are divided into training and test sets. This dataset is associated with the following publication: Cho, E., J. Buick, A. Williams, R. Chen, H. Li, C. Corton, A. Fornace, J. Aubrecht, and C. Yauk. Assessment of the performance of the TGx-DDI biomarker to detect DNA damage-inducing agents using quantitative RT- PCR in TK6 cells. ENVIRONMENTAL AND MOLECULAR MUTAGENESIS. John Wiley & Sons, Inc, Hoboken, NJ, USA, 60(2): 122-133, (2019).

Background Vitamin D has been shown to exert manifold immunomodulatory effects. Type 1 diabetes mellitus (T1DM) is regarded to be immune-mediated and vitamin D prevents the development of diabetes in the NOD mouse. We studied the association between T1DM and the initiation codon polymorphism in exon 2 of the vitamin D receptor gene in a Japanese population. We also investigated associations between the vitamin D receptor polymorphism and GAD65-antibody (Ab) positivity. We carried out polymerase chain reaction-restriction fragment length polymorphism analysis in 110 Japanese T1DM patients and 250 control subjects. GAD65 antibodies were assessed in 78 patients with T1DM. Results We found a significantly higher prevalence of the F allele / the FF genotype in the patients compared to the controls (P = 0.0069 and P = 0.014, respectively). Genotype and allele frequencies differed significantly between GAD65-Ab-positive patients and controls (P = 0.017 and P = 0.012, respectively), but neither between GAD65-Ab-negative patients and controls (P = 0.68 and P = 0.66, respectively) nor between GAD65-Ab-positive and -negative patients (P = 0.19 and P = 0.16, respectively). Conclusions Our findings suggest that the vitamin D receptor initiation codon polymorphism influences genetic susceptibility to T1DM among the Japanese. This polymorphism is also associated with GAD65-Ab-positive T1DM, although the absence of a significant difference between GAD65-Ab-negative patients and controls might be simply due to the small sample size of patients tested for GAD65 antibodies.