Salt-tolerant Pokkali rice plants accumulate higher polyamines (PAs) such as spermidine (Spd) and spermine (Spm) in response to salinity stress, while the sensitive cultivarM-1-48 is unable to maintain high titres of these PAs under similar conditions. The effects of the triamine Spd and the tetramine Spm on physiological and biochemical changes in 12-day-old rice seedlings were investigated during salinity stress to determine whether they could protect the sensitive plants from stress effects. At physiological concentrations Spd and Spm significantly prevented the leakage of electrolytes and amino acids from roots and shoots induced by salinity stress. To different degrees they also prevented chlorophyll loss, inhibition of photochemical reactions of photosynthesis as well as downregulation of chloroplast-encoded genes like psbA, psbB, psbE and rbcL, indicating a positive correlation between salt tolerance and accumulation of higher PAs in rice. The inhibitory effect of salinity stress and its reversal by exogenous PAs were more pronounced in the salt-sensitiveM-1-48 plants than in the tolerant Pokkali plants.
Foxp3+ T regulatory cells (Treg) are critically important for the maintenance of immunological tolerance, immune homeostasis and prevention of autoimmunity. Dendritic cells (DCs) are one of the major targets of Treg-mediated suppression. Some studies have suggested that Treg-mediated suppression of DC function is mediated by the interaction of CTLA-4 on Treg with CD80/CD86 on the DC resulting in down- regulation of CD80/CD86 expression and a decrease in co-stimulation. We have re-examined the effects of Treg on mouse DC function in a model in which antigen-specific, induced Treg (iTreg) are co-cultured with DC in the absence of Teff cells. iTreg-treated DC are markedly defective in their capacity to activate naïve T cells. iTreg from CTLA-4 deficient mice failed to induce downregulation of CD80/CD86, but DCs treated with CTLA-4 deficient iTreg still exhibited impaired capacity to activate naïve T cells. The iTreg-induced defect in DC function could be completely reversed by anti-IL-10 and IL-10 deficient iTregs failed to down-regulate DC function. iTreg-treated DCs expressed high levels of MARCH1, an E3 ubiquitin ligase, recently found to degrade CD86 and MHC-II on the DC and expressed lower levels of CD83, a molecule involved in neutralizing the function of MARCH1. Both the enhanced expression of MARCH1 and the decreased expression of CD83 were mediated by IL-10 produced by the iTreg. Taken together, these studies demonstrate that a major suppressive mechanism of DC function by iTreg is secondary to the effects of IL-10 on MARCH1 and CD83 expression.
IgG anti-polysaccharide (PS) responses to both intact Streptococcus pneumoniae (Pn) and PS conjugate vaccines are dependent on CD4+ T cells, B7-dependent costimulation, and CD40-CD40-ligand interactions. Nevertheless, the former response, in contrast to the latter, is mediated by an ICOS-independent, apoptosis-prone, extrafollicular pathway that fails to generate PS-specific memory. We show that pre-existing PS-specific Igs, the bacterial surface or particulation, selective recruitment of B cell subsets, or activation and recruitment of Pn protein-specific CD4+ T cells do not account for the failure of Pn to generate PS-specific IgG memory. Rather, the data suggest that the critical factor may be the lack of covalent attachment of PS to protein in intact Pn, highlighting the potential importance of the physicochemical relationship of PS capsule with the underlying bacterial structure for in vivo induction of PS-specific Igs.
Infectious mononucleosis and B-cell transformation in response to infection with Epstein-Barr virus (EBV) is dependent upon binding of the EBV envelope glycoprotein gp350 to CD21 on B-cells. Gp350-specific antibody comprises most of the EBV neutralizing activity in the serum of infected patients, making this protein a promising target antigen for a prophylactic EBV vaccine. We describe a novel, tetrameric gp350-based vaccine that exhibits markedly enhanced immunogenicity relative to its monomeric counterpart. Plasmid DNA was constructed for synthesis, within transfected CHO cells, of a tetrameric, truncated (a.a. 1-470) gp350 protein (gp3501-470). Tetrameric gp3501-470 induced ~20-fold higher serum titers of gp3501-470-specific IgG and >19-fold enhancements in neutralizing titers at the highest dose, and was >25-fold more immunogenic on a per-weight basis than monomeric gp3501-470. Further, epidermal immunization with plasmid DNA encoding gp3501-470 tetramer induced 8-fold higher serum titers of gp3501-470-specific IgG relative to monomer. Tetrameric gp3501-470 binding to human CD21 was >24-fold more efficient on a per-weight basis than monomer, but neither tetramer nor monomer mediated polyclonal human B-cell activation. Finally, the introduction of strong, universal tetanus toxoid (TT)-specific CD4+ T-cell epitopes into the tetrameric gp3501-470 had no effect on the gp3501-470-specific IgG response in naïve mice, and resulted in suppressed gp3501-470-specific IgG responses in TT-primed mice. Collectively, these data suggest that tetrameric gp3501-470 is a potentially promising candidate for testing as a prophylactic EBV vaccine, and that protein multimerization, using the approach described herein, is likely to be clinically relevant for enhancing the immunogenicity of other proteins of vaccine interest.
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