It is unclear if these CD8+ T cells

are at an early or late stage of differentiation and whether telomere erosion restricts their replicative capacity. We developed a multiparameter flow cytometric method for investigating the relationship between differentiation (CD45RA and CD27 surface phenotype), function (cytokine production) and replicative capacity (telomere length) in individual cytomegalovirus (CMV) antigen specific CD8+ T cells. This involves surface and intracellular cell staining coupled to fluorescence in situ hybridization to detect telomeres (flow-FISH). The end-stage/senescent CD8+ CD45RA+CD27- T cell subset increases significantly during ageing and this is exaggerated in CMV immune responsive subjects. However these end-stage cells do not have the shortest telomeres implicating additional non-telomere related mechanisms in inducing

their senescence. The telomere lengths in total and CMV(NLV)-specific Enzalutamide mw CD8+ T cells in all four subsets defined by CD45RA and CD27 expression were significantly shorter in old compared to young individuals in both a Caucasian and an Asian cohort. Following stimulation by anti-CD3 or NLV peptide, similar proportions of triple -cytokine producing cells are found in CD8+ T cells at all stages of differentiation in both age groups. Furthermore, these multifunctional cells had intermediate telomere lengths compared to cells producing only one or two cytokines after activation. Therefore, global and CMV (NLV)-specific JQ1 CD8+ T cells that secrete IFNγ, IL-2 and TNFα are at an intermediate stage of differentiation and are not restricted by excessive telomere erosion. This article is protected by copyright. All rights reserved. “
“Statins are widely used drugs for the treatment of hypercholesterolaemia. A number of recent studies

have suggested that statins also have pleiotropic effects on immune responses and statins have proven to be effective in the treatment of autoimmune diseases in animal models. Foxp3+ T regulatory cells are a unique subset of CD4+ T cells that mediate immunosuppression. Foxp3+ T cells develop in the thymus, but can also be induced in peripheral sites in the presence of transforming growth factor-β (TGF-β). We demonstrate here that simvastatin blockade of the mevalonate pathway can mediate induction Methane monooxygenase of mouse Foxp3+ T cells and that simvastatin can synergize with low levels of TGF-β to induce Foxp3+ T cells. The effects of simvastatin are secondary to a blockade of protein geranylgeranylation, are mediated at late time-points after T-cell activation, and are associated with demethylation of the Foxp3 promoter. One major effect of simvastatin was inhibition of the induction of Smad6 and Smad7, inhibitory Smads that inhibit TGF-β signalling. Our results suggest that one mechanism responsible for the immunosuppressive effects of statins is the ability to promote the generation of Foxp3+ T regulatory cells.