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The “other” mTOR complex: New insights into mTORC 2 immunobiology and their implications
Author(s) -
Dai Helong,
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.15320
Subject(s) - mtorc2 , medicine , pi3k/akt/mtor pathway , microbiology and biotechnology , mtorc1 , signal transduction , biology
A central role of the mechanistic target of rapamycin ( mTOR ) in regulation of fundamental cell processes is well recognized. mTOR functions in two distinct complexes: rapamycin‐sensitive mTOR complex (C) 1 and rapamycin‐insensitive mTORC 2. While the role of mTORC 1 in shaping immune responses, including transplant rejection, and the influence of its antagonism in promoting allograft tolerance have been studied extensively using rapamycin, lack of selective small molecule inhibitors has limited understanding of mTORC 2 biology. Within the past few years, however, intracellular localization of mTORC 2, its contribution to mitochondrial fitness, cell metabolism, cytoskeletal modeling and cell migration, and its role in differentiation and function of immune cells have been described. Studies in mTORC 2 knockdown/knockout mouse models and a new class of dual mTORC 1/2 inhibitors, have shed light on the immune regulatory functions of mTORC 2. These include regulation of antigen‐presenting cell, NK cell, T cell subset, and B cell differentiation and function. mTORC 2 has been implicated in regulation of ischemia/reperfusion injury and graft rejection. Potential therapeutic benefits of antagonizing mTORC 2 to inhibit chronic rejection have also been described, while selective in vivo targeting strategies using nanotechnology have been developed. We briefly review and discuss these developments and their implications.