Myeloid Dendritic Cell-Specific mTORC2 Deficiency Enhances Alloreactive Th1 and Th17 Cell Responses and Skin Graft Rejection.

Abstract

The mechanistic/mammalian target of rapamycin (RAPA) (mTOR) is a key integrative kinase that functions in at least two independent complexes: RAPA-sensitive mTOR complex (C)1 and RAPA-insensitive mTORC2. While mTORC2 in T cells promotes Th2 and Th17 differentiation, its immunologic function in dendritic cells (DC) is largely unknown. We defined the role of rictor, a key mTORC2 component, in myeloid DC and their ability to polarize interacting allogeneic Th cells. When stimulated with TLR ligands, bone marrow-derived DC generated from conditional rictor KOs displayed lower co-inhibitory B7-H1 (CD274) molecule expression, enhanced IL-12p70, IL-23, IL-6 and TNFa production and augmented allogeneic T cell stimulatory ability. Analysis of allopeptide-specific CD4+ T cells after activation by rictor KO DC in vivo revealed significant expansion of IFN-g+ and IL-17+, but not IL-10+ or CD4+Foxp3+ T cells. To assess the role of Rictor in host DC following transplantation, we grafted male WT skin on to DC-specific Rictor-KO female mice (generated using the Cre/LoxP system to knock out Rictor on CD11c+ cells). Female DC-specific Rictor-KO mice rejected male WT skin graft faster than controls (median survival times of 20d versus 27d, respectively). These data indicate that DC lacking mTORC2 activity exhibit an enhanced proinfl ammatory profile with ability to promote Th17 responses and accelerate skin graft rejection. Thus, targeting mTORC2 provides new insight into molecular regulation of DC function with therapeutic implications in transplantation.