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Type 1 diabetes is a T cell-mediated organ-specific autoimmune disease. Antigen-specific immune intervention allows the selective targeting of autoreactive T cell, while leaving the remainder of the immune system intact. However, immune intervention for type 1 diabetes has not yielded perfect results clinically. In our paper published previously, we asked whether pancreatic duodenal home box 1 (PDX1) is a target of anti-islet autoimmunity in type 1 diabetes. In this experiment, we assessed the therapeutic effect of oral administration of PDX1 on diabetes development of 4-week-old non-obese diabetic (NOD) mice. The results indicate that PDX1 immunization is an effective intervention strategy for delaying the onset of diabetes in NOD mice in association with: 1) reduced insulitis; 2) suppression of destructive autoreactive T cells; 3) augmentation of regulatory T cells; 4) a shift in cytokine production. The present observations suggest that immunization with PDX1 modulates immune cell responses in NOD mice, raising the possibility that it is beneficial in ameliorating autoimmune destruction of beta-cells and delaying type 1 diabetes development clinically. [ABSTRACT FROM AUTHOR]

Abstract: Metabolic bone diseases, such as rheumatoid arthritis (RA) and osteoporosis, affect hundreds and millions of people worldwide leading causes of long-term pain and disability. Effective clinical treatment for bone destruction in bone diseases is lacking because the knowledge about molecular mechanisms leading to bone destruction are incompletely understood. Recently, it has been confirmed that regulatory T cells (Tregs) play a crucial role in suppressing the immune response in the pathogenesis of various autoimmune diseases. In vitro, Tregs directly inhibit osteoclasts and differentiation and function. In mice, the injection of Tregs into the TNF transgenic results in enhanced systemic bone density. In addition, it has been shown that increase of Tregs numbers by overexpressing the FoxP3 is effective in the prevention of local and systemic bone destruction. In vivo treatment with anti-CD28 superagonist antibody leading to a stronger increase in Tregs numbers protect against TNF-a-induced bone loss in TNF-transgenic mice. In agreement, Tregs can control ovariectomy-induced bone loss in FoxP3-transgenic mice. In this paper, we will briefly discuss the biological features of Tregs and summarize recent advances on the role of Tregs in the pathogenesis and treatment of bone loss in metabolic bone diseases. [Copyright &y& Elsevier]

Abstract: Despite the fact that the negative regulatory element (NRE) within the upstream regulatory region of human IL-2 receptor α (IL-2Rα) gene has been identified two decades ago, mechanisms of the NRE function on the gene are hitherto unknown. In this paper, we report for the first time that the immunoglobulin transcription factor 2B (ITF2B) encoded by transcription factor 4 (TCF4) gene is a NRE binding protein. The full-length TCF4 cDNA clone was obtained from a HTLV-1 transformed human peripheral T cell MACHERMAKER cDNA library with NRE as the bait in yeast one-hybrid system. The NRE binding ability of ITF2B was further confirmed in chromatin-immunoprecipitation assay. Competitive RT-PCR-based promoter activity assay showed that over-expression of ITF2B protein inhibited the expression of IL-2Rα gene in Jurkat cells in an NRE-dependent manner. The function of ITF2B on the inhibition of both the IL-2Rα and the 5′LTR activity of HIV-1 shed light on the essence of NRE binding protein as a potential target for immune therapy and treatment in AIDS patients. [Copyright &y& Elsevier]

Abstract: Signaling pathways such as the pre-TCR and Wnt pathways regulate α/β T cell differentiation in thymus. Mice lacking an essential component of the pre-TCR exhibit arrest at the (CD4−CD8−) (CD44−CD25+) stage (DN3) of thymocyte development, and introduction of p53 deficiency into those mice abrogates this arrest, resulting in transition to the (CD4+CD8+) double-positive (DP) stage. This paper examines the effect of inactivation of p53 on thymocyte development in Bcl11b−/− mice that exhibit arrest at the DN3 or (CD4−CD8+) immature single-positive (ISP) stage. No DP thymocytes were detected in thymocytes of adoptive transfer experiments in scid mice that were derived from p53−/−Bcl11b−/− precursors but ISP thymocytes increased in the proportion and in the cell number approximately three times higher than those from Bcl11b−/− precursors. Consistently, the level of apoptosis decreased to the level of wild-type precursors. These results suggest that inactivation of p53 is sufficient for DN3 thymocytes to differentiate into the ISP, but not to DP, stage of thymocyte development in Bcl11b−/− mice. This provides evidence for a novel p53-mediated checkpoint that regulates the transition from the DN3 to ISP stage of thymocyte development. [Copyright &y& Elsevier]

The protein-tyrosine kinase p56lck is the product of the lck gene. It plays a pivotal role in T-lymphocyte activation and thymocyte development, as indicated by the defective immune responses of lck−/− mice. We have demonstrated that an exon 7-deleted lck mRNA is produced by alternative splicing in all human cells expressing the lck gene. We have now looked for the protein encoded by this spliced lck mRNA and attempted to determine the function of the deleted Lck protein. This paper shows that the LckΔ7 protein is present in JCaM1.6 T-cells and we inferred that this isoform accounts for 15% of the total Lck proteins in the parental Jurkat T-cell line. We report that deletion of the first 51 amino-acids (exon 7) of the Lck catalytic domain greatly reduces the kinase activity of the recombinant protein. The residual activity can, nevertheless, be enhanced by adding Mn2+, whereas this cation has no effect on the activity of the p56lck mutated in its active site (K273E). The enforced production of LckΔ7 protein in transfected Jurkat cells results in slower cell proliferation than does p56lck. These findings suggest that the LckΔ7 protein is a p56lck cell-signaling regulator. This mechanism could be common to both humans and mice, in which we also found the exon 7-spliced lck transcript. [Copyright &y& Elsevier]