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mTORC2 deficiency in cutaneous dendritic cells potentiates CD8 + effector T cell responses and accelerates skin graft rejection
Author(s) -
Watson Alicia R.,
Dai Helong,
DiazPerez Julio A.,
Killeen Meaghan E.,
Mathers Alicia R.,
Thomson Angus W.
Publication year - 2019
Publication title -
american journal of transplantation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.89
H-Index - 188
eISSN - 1600-6143
pISSN - 1600-6135
DOI - 10.1111/ajt.15083
Subject(s) - mtorc2 , cd8 , t cell , dendritic cell , cytotoxic t cell , immunology , mtorc1 , medicine , immune system , plasmacytoid dendritic cell , microbiology and biotechnology , pi3k/akt/mtor pathway , cancer research , biology , signal transduction , biochemistry , in vitro
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 DC−/− ), we show that the transplant of minor histocompatibility Ag (HY)‐mismatched skin grafts from TORC2 DC−/− donors into wild‐type recipients results in accelerated rejection characterized by enhanced CD8 + T cell responses in the graft and regional lymphoid tissue [Correction added on January 9, 2019, after first online publication: in the previous sentence, major was changed to minor]. Similar enhancement of CD8 + effector T cell responses was observed in MHC‐mismatched recipients of TORC2 DC−/− 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 DC−/− and not to enhanced lymph node homing of the cells. In contrast, rejection of ovalbumin transgenic skin grafts in TORC2 DC−/− 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.