Survival data were analyzed using the log-rank test. All other data were analyzed using one-way or two-way ANOVA with the Bonferroni post-test. Statistical analyses were performed with GraphPad Prism version 5. p≤0.05 was considered significant. www.selleckchem.com/products/azd3965.html We thank Leon Douglas for providing MHC I tetramers. This work was supported by grants from Cancer Research UK, Leukaemia and Lymphoma Research and the Association for International Cancer Research (to A. Al-S.). Conflict of interest: The authors declare no financial or commercial conflict of interest.

Detailed facts of importance to specialist readers are published as ”Supporting Information”. Such documents are peer-reviewed, but not copy-edited or typeset. They are made available as submitted by the authors. “
“Suppressors of cytokine signalling (SOCS) proteins are induced in responses to many stimuli and by binding to cytokine receptors and associated janus kinase (JAK) proteins, directly regulate the activation of the signal transducers and activators of transcription (STATs). STAT proteins check details regulate the expression of many genes required for the differentiation of various CD4+ T helper cell lineages, and there is now accumulating evidence that

SOCS also play essential roles in the regulation and maintenance of CD4+ T-cell polarization. As it is now clear that CD4+ T cells are more plastic than initially thought, it is of particular importance to understand the molecular mechanisms regulating CD4+ T-cell differentiation. Here we review the current understanding of how STATs and SOCS act in concert to influence the polarization of CD4+ T cells and highlight the relevance of this in disease.

After interaction with their cognate antigen, naive CD4+ T cells proliferate and, depending on the cytokine micro-environment, polarize towards different CD4+ lineages, which then shape the immune response. CD4+ lineages include T helper type 1 (Th1), which drives the immune response against intracellular pathogens, Th2, which promotes humoral responses, Th17 cells, which contribute to the elimination of extracellular pathogens, and Foxp3+ regulatory T (Treg) cells, which prevent the development of autoimmunity (Fig. 1a). The differentiation towards each lineage is associated with the Silibinin up-regulation of specific transcription factors that act as master regulators by controlling the expression of a panel of genes, conferring a specific phenotype1 (Fig. 1a). There is accumulating evidence that CD4+ T-cell lineages are not as stable as initially thought, but rather, in specific environments, secrete cytokines and co-express master regulators specific for other lineages.2 The factors that control CD4+ T-cell stability versus plasticity are currently poorly understood, but it is clear that signal transducer and activator of transcription (STAT) proteins play key roles in this process.