mTORC2 deficiency in cutaneous dendritic cells potentiates CD8+ effector T cell responses and accelerates skin graft rejection

Abstract

Mechanistic target of rapamycin (mTOR) complex (mTORC)1 and mTORC2 regulate the differentiation and function of immune cells. While inhibition of mTORC1 antagonizes dendritic cell (DC) differentiation and suppresses graft rejection, the role of mTORC2 in DCs in determining host responses to transplanted tissue remains undefined. Using a mouse model in which mTORC2 was deleted specifically in CD11c DCs (TORC2 ), we show that the transplant of major histocompatibility Ag (HY)-mismatched skin grafts from TORC2 donors into wild-type recipients results in accelerated rejection characterized by enhanced CD8 T cell responses in the graft and regional lymphoid tissue. Similar enhancement of CD8 effector T cell responses was observed in MHC-mismatched recipients of TORC2 grafts. Augmented CD8 T cell responses were also observed in a delayed-type hypersensitivity model in which mTORC2 was absent in cutaneous DCs. These elevated responses could be ascribed to an increased T cell stimulatory phenotype of TORC2 and not to enhanced lymph node homing of the cells. In contrast, rejection of ovalbumin transgenic skin grafts in TORC2 recipients was unaffected. These findings suggest that mTORC2 in skin DCs restrains effector CD8 T cell responses and have implications for understanding of the influence of mTOR inhibitors that target mTORC2 in transplant.

The “other” mTOR complex: New insights into mTORC2 immunobiology and their implications

“…Therapeutically, intra-tumoral Rictor −/− DC injection inhibits B16 melanoma growth in wt B6 mice by promoting interferon (IFN)-γ and granzyme-B + cytotoxic CD8 + T cell infiltration into the tumor 25 . In agreement with these findings, CD8 + T effector cell responses are augmented in skin grafts transplanted from major histocompatibility complex (MHC)-or minor histocompatibility antigen (Ag) (HY)-mismatched CD11c Rictor −/− donors 26 , with the latter undergoing accelerated rejection. In the absence of Rictor specifically in cutaneous DC, CD8 + T cell responses are also enhanced in a mouse cutaneous delayed-type hypersensitivity model 26 .…”

Regulation of Dendritic Cell Immune Function and Metabolism by Cellular Nutrient Sensor Mammalian Target of Rapamycin (mTOR)

“…In contrast to the studies above, we and other have shown that mTOR inhibition can enhance T cell stimulatory capacity in certain contexts (11, 15, 50, 69). mTORC2 deficiency has been documented to augment CD8+ lymphocyte -mediated graft rejection in mice (70), while mice given autologous DCs simulated with LPS in the presences of rapamycin led to a negative impact on T lymphocyte activation and improved graft vs. host survival (71). In GM-CSF -differentiated BMDCs, both mTOR inhibitors enhance LPS-driven DC activation and T cell stimulatory capacity, at least in part through attenuation of mTOR-dependent nitric oxide generation (11, 15).…”

mTORC2 Deficiency Alters the Metabolic Profile of Conventional Dendritic Cells

“…We and others have reported previously (13, 43) that murine myeloid DC lacking functional TORC2 display an augmented pro-inflammatory phenotype and enhance Th1/Th17 and CD8 + effector T cell responses in vivo (13–15). Similar observations have been reported for mouse macrophages (44).…”

“…While little had been known previously about the function of RAPA-insensitive mTORC2 (referred to subsequently as TORC2) specifically in DC, we have shown recently that functional TORC2 deletion specifically in these antigen-presenting cells (APC) leads to both an enhanced pro-inflammatory DC phenotype and Th1/Th17 allogeneic T cell polarization and proliferation (13). Additionally, intratumoral delivery of TORC2-deficient DC delays melanoma progression in a CD8 + T cell-dependent manner (14), whereas skin grafts from donors lacking TORC2 in DC undergo enhanced CD8 + T cell-mediated rejection (15). However, the mechanisms underlying these enhanced DC functions remain undefined.…”