Mammalian target of rapamycin (mTOR) is an important, yet poorly understood 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, an essential component of mTORC2, but not mTORC1). Bone marrow cells were obtained from KO and WT B6 controls, and myeloid 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. Flow cytometry was used to determine responder T cell phenotype and cytokine production.
DC differentiation was not affected, while DC yield was reduced slightly in Rictor-(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, increased levels of IL-12p40, diminished STAT3 activation and higher T cell stimulatory ability following LPS stimulation, compared with WT controls. Staining of allogeneic T cells stimulated by Rictor-KO DC revealed an increased incidence of CD4+ IL-17+ cells compared with those stimulated with WT DC.
These novel data indicate that DC lacking mTORC2 activity exhibit an enhanced pro-inflammatory profile with ability to promote Th17 responses. Thus, targeting mTORC2 in DC elicits a unique immune modulation profile, compared with targeting mTORC1, providing new insight into molecular regulation of DC function with therapeutic implications in transplantation.
To cite this abstract in AMA style:Raich-Regue D, Rosborough B, Lee K, Boothby M, Turnquist H, Thomson A. Targeting of mTORC2 in DC Elicits an Enhanced Pro-Inflammatory Profile and Th17 Alloresponse [abstract]. Am J Transplant. 2013; 13 (suppl 5). http://atcmeetingabstracts.com/abstract/targeting-of-mtorc2-in-dc-elicits-an-enhanced-pro-inflammatory-profile-and-th17-alloresponse/. Accessed November 19, 2017.
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