Evolving perspectives of mTOR complexes in immunity and transplantation

Since the discovery of Rapamycin (RAPA) and its immunosuppressive properties, enormous progress has been made in characterizing the mechanistic target of rapamycin (mTOR). Use of RAPA and its analogues (rapalogs) as anti-rejection agents has been accompanied by extensive investigation of how targeting of mTOR complex 1 (mTORC1), the principal target of RAPA, and more recently mTORC2, affects the function of immune cells, as well as vascular endothelial cells, that play crucial roles in regulation of allograft rejection. While considerable knowledge has accumulated on the function of mTORC1 and 2 in T cells, understanding of the differential roles of these complexes in antigen-presenting cells, NK cells and B cells/plasma cells is only beginning to emerge. Immune cell-specific targeting of mTORC1 or mTORC2, together with use of novel, second generation, dual mTORC kinase inhibitors (TORKinibs) have started to play an important role in elucidating the roles of these complexes and their potential for targeting in transplantation. Much remains unknown about the role of mTOR complexes and the consequences of mTOR targeting on immune reactivity in clinical transplantation. Here we address recent advances in understanding and evolving perspectives of the role of mTOR complexes and mTOR targeting in immunity, with extrapolation to transplantation.