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Vibrio vulnificus (V. vulnificus), a Gram-negative marine bacterium, can cause life-threatening primary septicemia, especially in patients with liver diseases. How V. vulnificus affects the liver and how it acts on macrophages are not well understood. In this report, we demonstrated that V. vulnificus infection causes a strong inflammatory response, marked expansion of liver-resident macrophages, and liver damage in mice. We demonstrated further that V. vulnificus activates mTOR in macrophages and inhibition of mTOR differentially regulates V. vulnificus induced inflammatory responses, suggesting the possibility of targeting mTOR as a strategy to modulate V. vulnificus induced inflammatory responses. [ABSTRACT FROM AUTHOR]

Accumulating evidence indicates that the tuberous sclerosis complex 1 (TSC1), a tumor suppressor that acts by inhibiting mTOR signaling, plays an important role in the immune system. We report here that TSC1 differentially regulates mTOR complex 1 (mTORC1) and mTORC2/Akt signaling in B cells. TSC1 deficiency results in the accumulation of transitional-1 (T1) B cells and progressive losses of B cells as they mature beyond the T1 stage. Moreover, TSC1KO mice exhibit a mild defect in the serum antibody responses or rate of Ig class-switch recombination after immunization with a T-cell-dependent antigen. In contrast to a previous report, we demonstrate that both constitutive Peyer’s patch germinal centers (GCs) and immunization-induced splenic GCs are unimpaired in TSC1-deficient (TSC1KO) mice and that the ratio of GC B cells to total B cells is comparable in WT and TSC1KO mice. Together, our data demonstrate that TSC1 plays important roles for B cell development, but it is dispensable for GC formation and serum antibody responses. [ABSTRACT FROM AUTHOR]

The engagement of the T cell receptor (TCR) induces the generation of diacylglycerol (DAG), an important second messenger activating both the Ras/Erk and PKCθ/NFκB pathways. DAG kinases (DGKs) participate in the metabolism of DAG by converting it to phosphatidic acid. DGKζ has been demonstrated to be able to inhibit DAG signaling following TCR engagement. Deficiency of DGKζ increases the sensitivity of T cells to TCR stimulation, resulting in enhanced T cell activation ex vivo and in vivo. However, the mechanisms that control DGKζ expression are poorly understood. Here we demonstrate that DGKζ mRNA is a direct target of a cellular microRNA miR-34a. The DGKζ transcript is decreased, whereas the primary miR-34a is upregulated upon TCR stimulation. Ectopic miR-34a expression suppresses DGKζ protein expression through the seed match binding to both the 3' untranslated region and coding region of DGKζ mRNA, leading to increased ERK1/2 phosphorylation and surface expression of the T cell activation marker CD69 following TCR cross-linking. In contrast, overexpression of a miR-34a competitive inhibitor increases DGKζ expression and suppresses TCR-mediated T cell activation. Together, our data demonstrate that miR-34a is a negative regulator for DGKζ and may play an important role in regulating T cell activation. [ABSTRACT FROM AUTHOR]

Invariant natural killer T (iNKT) cells play important roles in bridging innate and adaptive immunity via rapidly producing a variety of cytokines. A small subset of iNKT cells produces IL-17 and is generated in the thymus during iNKT-cell ontogeny. The mechanisms that control the development of these IL-17-producing iNKT-17 cells (iNKT-17) are still not well defined. Diacylglycerol kinase ζ (DGKζ) belongs to a family of enzymes that catalyze the phosphorylation and conversion of diacylglycerol to phosphatidic acid, two important second messengers involved in signaling from numerous receptors. We report here that DGKζ plays an important role in iNKT-17 development. A deficiency of DGKζ in mice causes a significant reduction of iNKT-17 cells, which is correlated with decreased RORγt and IL-23 receptor expression. Interestingly, iNKT-17 defects caused by DGKζ deficiency can be corrected in chimeric mice reconstituted with mixed wild-type and DGKζ-deficient bone marrow cells. Taken together, our data identify DGKζ as an important regulator of iNKT-17 development through iNKT-cell extrinsic mechanisms. [ABSTRACT FROM AUTHOR]