The T-cell subsets, characterized by their cytokine production profiles and immune regulatory functions, depend on correct in vivo location to interact with accessory or target cells for effective immune responses. Differentiation of naive CD4 1 T cells into effectors is accompanied by sequentially regulated expression of the chemokine receptors responsible for cell recruitment to specific tissues. We studied CCR6 function in EAE, a CD4 1 T-cell-mediated CNS disease characterized by mononuclear infiltration and demyelination. CCR6 À/À mice showed an altered time course of EAE development, with delayed onset, a higher clinical score, and more persistent symptoms than in controls. An imbalanced cytokine profile and reduced Foxp3 1 cell frequency characterized CNS tissues from CCR6 À/À compared with CCR6 1/1 mice during the disease effector phase. Transfer of CCR6 1/1 Treg to CCR6 À/À mice the day before EAE induction reduced the clinical score associated with an increased in infiltrating Foxp3 1 cells and recovery of the cytokine balance in CCR6 À/À mouse CNS. Competitive assays between CCR6 1/1 and CCR6 À/À Treg adoptively transferred to CCR6 À/À mice showed impaired ability of CCR6 À/À Treg to infiltrate CNS tissues in EAE-affected mice. Our data indicate a CCR6 requirement by CD4 1 Treg to downregulate the CNS inflammatory process and neurological signs associated with EAE.Key words: Chemokines . EAE/MS . Inflammation . T cells Introduction EAE is a CNS disease characterized by mononuclear cell infiltration and demyelination; it is used to study certain aspects of human MS. EAE can be induced via immunization with neural antigens such as myelin oligodendrocyte glycoprotein (MOG). The immunopathological event in EAE and MS initiates when autoreactive T cells in the systemic immune compartment are activated and cross the blood-brain barrier [1]. Re-encounter of encephalitogenic T cells with their antigen leads to reactivation and expansion of autoreactive T cells, which in turn stimulate microglia/astrocyte activity, with increased release of proinflammatory cytokines and chemokines. The action of these mediators leads to demyelination and axon degeneration [2,3]. After antigen contact, naive CD4 1 T cells differentiate into various effector-cell subsets characterized by the cytokines they produce and by their immune regulatory functions. Th1 and Th17 cytokine profile effector cells and antigen-specific Treg have a critical role in EAE pathogenesis [4][5][6][7][8][9][10]. In MOG-induced EAE, both antigen-specific T-effector and Treg differentiate and proliferate in the periphery before migrating to the CNS [9]. Differentiation is accompanied by sequential expression of selectins, integrins, and chemokine receptors responsible for T-cell-subset recruitment to and extravasation at inflammation sites. The correct in vivo location of these cell subsets, necessary for their interaction with accessory or target cells, is regulated by [11], which are assumed to have a critical impact on MS and EAE pathogenesis [12]. St...

The statins, a group of inhibitors of the 3-hydroxy-3-methylglutaryl coenzyme A reductase, are reported to influence a variety of immune system activities through 3-hydroxy-3-methylglutaryl coenzyme A reductase-dependent and -independent mechanisms. How statin treatment regulates immune system function in vivo nonetheless remains to be fully defined. We analyzed the immunomodulatory effects of lovastatin in a Candida albicans-induced delayed-type hypersensitivity reaction in mice. In this model, lovastatin administration reduced the acute inflammatory response elicited by C. albicans challenge. This anti-inflammatory activity of lovastatin was associated with a shift from a Th1 to a Th2 immune response, as well as an increase in the percentage of regulatory T cells at the inflammation site and in the regional draining lymph node. The lovastatin-induced increase in regulatory T cells in the inflamed skin was dependent on expression of CCL1, a chemokine that is locally up-regulated by statin administration. The anti-inflammatory effect of lovastatin was abrogated in CCL1-deficient mice. These results suggest that local regulation of chemokine expression may be an important process in statin-induced modulation of the immune system.

SummaryTransition from symmetric to asymmetric cell division requires precise coordination of differential gene expression. We show that embryonic stem cells (ESCs) mainly express DIDO3 and that their differentiation after leukemia inhibitory factor withdrawal requires DIDO1 expression. C-terminal truncation of DIDO3 (Dido3ΔCT) impedes ESC differentiation while retaining self-renewal; small hairpin RNA-Dido1 ESCs have the same phenotype. Dido3ΔCT ESC differentiation is rescued by ectopic expression of DIDO3, which binds the Dido locus via H3K4me3 and RNA POL II and induces DIDO1 expression. DIDO1, which is exported to cytoplasm, associates with, and is N-terminally phosphorylated by PKCiota. It binds the E3 ubiquitin ligase WWP2, which contributes to cell fate by OCT4 degradation, to allow expression of primitive endoderm (PE) markers. PE formation also depends on phosphorylated DIDO3 localization to centrosomes, which ensures their correct positioning for PE cell polarization. We propose that DIDO isoforms act as a switchboard that regulates genetic programs for ESC transition from pluripotency maintenance to promotion of differentiation.

Beyond their ability to inhibit cholesterol biosynthesis, the statins have pleiotropic effects that include anti-inflammatory and immunomodulatory activities. Statins could have clinical utility, alone or in combination with other chemotherapeutics, in the treatment of cancer. The mechanisms that underlie the anti-tumor activity of the statins are nonetheless poorly defined. No studies have analyzed how they alter the tumor-associated leukocyte infiltrate, a central factor that influences tumor stroma and cancer evolution. Here we used HER2/neu transgenic (Tg-neu) mice to analyze the effect of lovastatin (Lov) on the inflammatory reaction of spontaneous mammary tumors. Lov treatment of tumor-bearing Tg-neu mice did not alter growth of established tumors, but significantly reduced the number of new oncogenic lesions in these mice. Moreover, Lov inhibited the growth of newly implanted Tg-neu tumors in immunocompetent but not in immunodeficient mice. We found that Lov enhanced tumor infiltration by effector T cells, and reduced the number of immunosuppressive and pro-angiogenic M2-like tumor-associated macrophages (TAM). Concomitantly, the drug improved the structure and function of the tumor vasculature, measured as enhanced tumor oxygenation and penetration of cytotoxic drugs. Microarray analysis identified a Lov-elicited genetic program in Tg-neu tumors that might explain these effects; we observed Lov-induced downregulation of placental growth factor, which triggers aberrant angiogenesis and M2-like TAM polarization. Our results identify a role for lovastatin in the shaping and re-education of the inflammatory infiltrate in tumors, with functional consequences in angiogenesis and antitumor immunity.