Regulatory mechanisms involving CD8+ T cells (CD8 regulatory T cells (Tregs)) are important in the maintenance of immune homeostasis. However, the inability to generate functional CD8 Treg clones with defined Ag specificity has precluded a direct demonstration of CD8 Treg-mediated regulation. In the present study, we describe the isolation of functional lines and clones representing a novel population of TCRalphabeta+ Tregs that control activated Vbeta8.2+ CD4 T cells mediating experimental autoimmune encephalomyelitis. They express exclusively the CD8alphaalpha homodimer and recognize a peptide from a conserved region of the TCR Vbeta8.2 chain in the context of the Qa-1a (CD8alphaalpha Tregs). They secrete type 1 cytokines but not IL-2. CD8alphaalpha Tregs kill activated Vbeta8.2+ but not Vbeta8.2- or naive T cells. The CD8alphaalpha Tregs prevent autoimmunity upon adoptive transfer or following in vivo activation. These findings reveal an important negative feedback regulatory mechanism targeting activated T cells and have implications in the development of therapeutic strategies for autoimmune diseases and transplantation.
The rapid development of nanotechnology will inevitably release nanoparticles (NPs) into the environment with unidentified consequences. In addition, the potential toxicity of CeO2 NPs to plants, and the possible transfer into the food chain, are still unknown. Corn plants (Zea mays) were germinated and grown in soil treated with CeO2 NPs at 400 or 800 mg/kg. Stress related parameters, such as: H2O2, catalase (CAT) and ascorbate peroxidase (APX) activity, heat shock protein 70 (HSP 70), lipid peroxidation, cell death and leaf gas exchange were analyzed at 10, 15, and 20 days post germination. Confocal laser scanning microscopy was used to image H2O2 distribution in corn leaves. Results showed that the CeO2 NP treatments increased accumulation of H2O2, up to day 15, in phloem, xylem, bundle sheath cells, and epidermal cells of shoots. The CAT and APX activities were also increased in the corn shoot, concomitant with the H2O2 levels. Both 400 and 800 mg/kg CeO2 NPs triggered the up regulation of the HSP 70 in roots, indicating a systemic stress response. None of the CeO2 NPs increased the level of thiobarbituric acid reacting substances, indicating that no lipid peroxidation occurred. CeO2 NPs, at both concentrations, did not induce ion leakage in either roots or shoots, suggesting membrane integrity was not compromised. Leaf net photosynthetic rate, transpiration, and stomatal conductance were not affected by CeO2 NPs. Our results suggest that the CAT, APX and HSP 70 might help the plants defend against CeO2 NPs induced oxidative injury and survive NP exposure.
CD8αα+CD4−TCRαβ+ T cells are a special lineage of T cells found predominantly within the intestine as intraepithelial lymphocytes and have been shown to be involved in the maintenance of immune homeostasis. Although these cells are independent of classical MHC class I (class Ia) molecules, their origin and function in peripheral lymphoid tissues are unknown. We have recently identified a novel subset of nonintestinal CD8αα+CD4−TCRαβ+ regulatory T cells (CD8αα Tregs) that recognize a TCR peptide from the conserved CDR2 region of the TCR Vβ8.2-chain in the context of a class Ib molecule, Qa-1a, and control- activated Vβ8.2+ T cells mediating experimental autoimmune encephalomyelitis. Using flow cytometry, spectratyping, and real-time PCR analysis of T cell clones and short-term lines, we have determined the TCR repertoire of the CD8αα regulatory T cells (Tregs) and found that they predominantly use the TCR Vβ6 gene segment. In vivo injection of anti-TCR Vβ6 mAb results in activation of the CD8αα Tregs, inhibition of the Th1-like pathogenic response to the immunizing Ag, and protection from experimental autoimmune encephalomyelitis. These data suggest that activation of the CD8αα Tregs present in peripheral lymphoid organs other than the gut can be exploited for the control of T cell-mediated autoimmune diseases.
Because Mycobacterium bovis, termed bacillus Calmette-Guérin (BCG), the only available used tuberculosis (TB) vaccine, retains immunomodulatory properties that limit its protective immunogenicity, there are continuous efforts to identify the immunosuppression mechanism as well as new strategies for improving the immunogenicity of BCG. Here, an ssDNA aptamer "antibody" BM2 specifically bound to the mannose-capped lipoarabinomannan (ManLAM) of BCG was selected. BM2 significantly blocked ManLAM-mannose receptor (MR) binding, triggered ManLAM-CD44 signaling, and enhanced M1 macrophage and Th1 activation via cellular surface CD44 in vitro and in vivo. BM2 enhanced immunoprotective effects of BCG against virulent Mycobacterium tuberculosis H37Rv infection in mice and monkeys models. Thus, we report a new mechanism of the interaction between ManLAM and CD44 on macrophages and CD4(+) T cells and reveal that ManLAM-binding membrane molecule CD44 is a novel target for the enhancement of BCG immunogenicity, and BM2 has strong potential as an immune enhancer for BCG.
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