Functional ESCRT machinery is required for constitutive recycling of claudin-1 and maintenance of polarity in vertebrate epithelial cells.

Genetic screens in Drosophila have identified regulators of endocytic trafficking as neoplastic tumor suppressor genes. For example, Drosophila endosomal sorting complex required for transport (ESCRT) mutants lose epithelial polarity and show increased cell proliferation, suggesting that ESCRT proteins could function as tumor suppressors. In this study, we show for the for the first time to our knowledge that ESCRT proteins are required to maintain polarity in mammalian epithelial cells.

The S1P(1)-mTOR axis directs the reciprocal differentiation of T(H)1 and T(reg) cells.

Naive CD4(+) T cells differentiate into diverse effector and regulatory lineages to orchestrate immunity and tolerance. Here we found that the differentiation of proinflammatory T helper type 1 (T(H)1) cells and anti-inflammatory Foxp3(+) regulatory T cells (T(reg) cells) was reciprocally regulated by S1P(1), a receptor for the bioactive lipid sphingosine 1-phosphate (S1P). S1P(1) inhibited the generation of extrathymic and natural T(reg) cells while driving T(H)1 development in a reciprocal manner and disrupted immune homeostasis.

Cutting edge: critical role for PYCARD/ASC in the development of experimental autoimmune encephalomyelitis.

Multiple sclerosis is an autoimmune disease in which self-reactive T cells attack oligodendrocytes that myelinate axons in the CNS. Experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis, is dependent on caspase-1; however, the role of Nod-like receptors upstream of caspase-1 is unknown. Danger- and pathogen-associated molecular patterns activate Nod-like receptor 3, which activates caspase-1 through the adaptor protein, apoptosis-associated speck-like protein containing CARD (ASC).

The receptor S1P1 overrides regulatory T cell-mediated immune suppression through Akt-mTOR.

Regulatory T cells (T(reg) cells) are critically involved in maintaining immunological tolerance, but this potent suppression must be 'quenched' to allow the generation of adaptive immune responses. Here we report that sphingosine 1-phosphate (S1P) receptor type 1 (S1P1) delivers an intrinsic negative signal to restrain the thymic generation, peripheral maintenance and suppressive activity of T(reg) cells. Combining loss- and gain-of-function genetic approaches, we found that S1P1 blocked the differentiation of thymic T(reg) precursors and function of mature T(reg) cells and affected T(reg) cell-mediated immune tolerance.