The research leading to these results has received funding from the European Union’s Seventh Framework Programme (FP7/2007–2013) under grant agreement
241779, and the European Leukodystrophy Association. The NIMBL Consortium comprises David Bonthron, Genetics Section, Leeds Institute of Molecular Medicine (LIMM), St James’s University Hospital, Leeds, UK; Antonio Celada, Institute for Research in Biomedicine (IRB) Barcelona, Spain; Yanick Crow, Genetic Medicine, Manchester Academic Health Science Centre, Manchester, UK; Taco Kuijpers, Academic Medical Center, University of Amsterdam, MG-132 concentration Amsterdam, The Netherlands; Arn van den Maagdenberg, Departments of Human Genetics and Neurology, Leiden University Medical Centre, Leiden, The Netherlands; Simona Orcesi, Department of Child Neurology and Psychiatry, IRCCS C. Mondino Institute of Neurology Foundation, Pavia, Italy; Dan Stetson, Department of Immunology, University of Washington, Seattle, WA, USA; Adeline Vanderver, Children Research Institute, Washington DC, USA. All authors report no disclosures. “
“Mammalian Sin1 ICG-001 ic50 plays key roles in the regulation of mitogen-activated protein kinase (MAPK) and mammalian target of rapamycin (mTOR) signaling. Sin1 is an essential component of mTOR complex 2 (mTORC2). The functions of Sin1 and mTORC2 remain
largely unknown in T cells. Here, we investigate Sin1 function in T cells using mice that lack Sin1 in the hematopoietic system. Sin1 deficiency blocks the mTORC2-dependent Akt phosphorylation in T cells during development and activation. Sin1-deficient T cells exhibit normal thymic cellularity and percentages of double-negative, double-positive, and single-positive CD4+ and CD8+ thymocytes. Sin1 deficiency does not impair T-cell receptor (TCR) induced growth and proliferation. Sin1 appears dispensable
for in vitro CD4+ helper cell differentiation. However, Sin1 deficiency results in an increased proportion of Foxp3+ natural Fenbendazole T-regulatory (nTreg) cells in the thymus. The TGF-β-dependent differen-tiation of CD4+ T cells in vitro is enhanced by the inhibition of mTOR but not by loss of Sin1 function. Our results reveal that Sin1 and mTORC2 are dispensable for the development and activation of T cells but play a role in nTreg-cell differentiation. Mammalian target of rapamycin (mTOR) is a conserved serine/threonine protein kinase that regulates cell growth and metabolism []. Mammalian TOR is inhibited by rapamycin, a potent suppressor of T cell-mediated immune responses []. Rapamycin inhibits IL-2-dependent T-cell proliferation, promotes the expansion of regulatory T (Treg) cells and has recently been shown to promote the development of memory CD8+ T cells [[3-5]].