Mammalian target of rapamycin (mTOR) is an important integrative kinase that regulates immune cel... more Mammalian target of rapamycin (mTOR) is an important integrative kinase that regulates immune cell function. mTOR functions in two independent complexes: mTOR complex (mTORC) 1 and 2. The immunosuppressant Rapamycin inhibits mTORC1 but not mTORC2. Our aim was to study the immune regulatory role and underlying mechanistic properties of mTORC2 in DC. We generated a conditional mTORC2 knockout, targeting Rictor. Bone marrow cells were obtained from KO and WT B6 controls, and DC propagated in the presence of IL-4 and GM-CSF, with or without LPS. The phenotype, cytokine production, STAT3 activation and ability of DC to induce allogeneic T cell proliferation were evaluated, and also the responder T cell phenotype and cytokine production. DC differentiation was not affected, while DC yield was slightly reduced in mTORC2-deficient BM cultures compared with WT controls. DC lacking mTORC2 activity displayed similar levels of MHC and co-stimulatory molecules, but diminished B7-H1 expression, i...
Journal of immunology (Baltimore, Md. : 1950), Sep 25, 2016
Allergic airway diseases are immune disorders associated with heightened type 2 immune responses ... more Allergic airway diseases are immune disorders associated with heightened type 2 immune responses and IL-5 and IL-13 production at the site of inflammation. We have previously reported that cyclooxygenase (COX) inhibition by indomethacin augmented allergic airway inflammation in a STAT6-independent manner. However, the key COX product(s) responsible for restraining indomethacin-mediated STAT6-independent allergic inflammation is unknown. In this study, using the mouse model of OVA-induced allergic airway inflammation, we identified that PGI2 receptor (IP) signaling was critical for indomethacin-induced, STAT6-independent proallergic effects. We demonstrated that IP deficiency increased inflammatory cell infiltration, eosinophilia, and IL-5 and IL-13 expression in the lung in a STAT6-independent manner. The augmented STAT6-independent allergic inflammation correlated with enhanced primary immune responses to allergic sensitization and elevated production of multiple inflammatory chemo...
Journal of immunology (Baltimore, Md. : 1950), 2015
The mammalian target of rapamycin (mTOR) senses and incorporates different environmental cues via... more The mammalian target of rapamycin (mTOR) senses and incorporates different environmental cues via the two signaling complexes mTOR complex 1 (mTORC1) and mTORC2. As a result, mTOR controls cell growth and survival, and also shapes different effector functions of the cells including immune cells such as T cells. We demonstrate in this article that invariant NKT (iNKT) cell development is controlled by mTORC2 in a cell-intrinsic manner. In mice deficient in mTORC2 signaling because of the conditional deletion of the Rictor gene, iNKT cell numbers were reduced in the thymus and periphery. This is caused by decreased proliferation of stage 1 iNKT cells and poor development through subsequent stages. Functionally, iNKT cells devoid of mTORC2 signaling showed reduced number of IL-4-expressing cells, which correlated with a decrease in the transcription factor GATA-3-expressing cells. However, promyelocytic leukemia zinc-finger (PLZF), a critical transcription factor for iNKT cell developm...
Mammalian target of rapamycin (mTOR) is an important integrative kinase that regulates immune cel... more Mammalian target of rapamycin (mTOR) is an important integrative kinase that regulates immune cell function. mTOR functions in two independent complexes: mTOR complex (mTORC) 1 and 2. The immunosuppressant Rapamycin inhibits mTORC1 but not mTORC2. Our aim was to study the immune regulatory role and underlying mechanistic properties of mTORC2 in DC. We generated a conditional mTORC2 knockout, targeting Rictor. Bone marrow cells were obtained from KO and WT B6 controls, and DC propagated in the presence of IL-4 and GM-CSF, with or without LPS. The phenotype, cytokine production, STAT3 activation and ability of DC to induce allogeneic T cell proliferation were evaluated, and also the responder T cell phenotype and cytokine production. DC differentiation was not affected, while DC yield was slightly reduced in mTORC2-deficient BM cultures compared with WT controls. DC lacking mTORC2 activity displayed similar levels of MHC and co-stimulatory molecules, but diminished B7-H1 expression, i...
Journal of immunology (Baltimore, Md. : 1950), Sep 25, 2016
Allergic airway diseases are immune disorders associated with heightened type 2 immune responses ... more Allergic airway diseases are immune disorders associated with heightened type 2 immune responses and IL-5 and IL-13 production at the site of inflammation. We have previously reported that cyclooxygenase (COX) inhibition by indomethacin augmented allergic airway inflammation in a STAT6-independent manner. However, the key COX product(s) responsible for restraining indomethacin-mediated STAT6-independent allergic inflammation is unknown. In this study, using the mouse model of OVA-induced allergic airway inflammation, we identified that PGI2 receptor (IP) signaling was critical for indomethacin-induced, STAT6-independent proallergic effects. We demonstrated that IP deficiency increased inflammatory cell infiltration, eosinophilia, and IL-5 and IL-13 expression in the lung in a STAT6-independent manner. The augmented STAT6-independent allergic inflammation correlated with enhanced primary immune responses to allergic sensitization and elevated production of multiple inflammatory chemo...
Journal of immunology (Baltimore, Md. : 1950), 2015
The mammalian target of rapamycin (mTOR) senses and incorporates different environmental cues via... more The mammalian target of rapamycin (mTOR) senses and incorporates different environmental cues via the two signaling complexes mTOR complex 1 (mTORC1) and mTORC2. As a result, mTOR controls cell growth and survival, and also shapes different effector functions of the cells including immune cells such as T cells. We demonstrate in this article that invariant NKT (iNKT) cell development is controlled by mTORC2 in a cell-intrinsic manner. In mice deficient in mTORC2 signaling because of the conditional deletion of the Rictor gene, iNKT cell numbers were reduced in the thymus and periphery. This is caused by decreased proliferation of stage 1 iNKT cells and poor development through subsequent stages. Functionally, iNKT cells devoid of mTORC2 signaling showed reduced number of IL-4-expressing cells, which correlated with a decrease in the transcription factor GATA-3-expressing cells. However, promyelocytic leukemia zinc-finger (PLZF), a critical transcription factor for iNKT cell developm...
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Papers by Mark Boothby