LAUSR

T mammalian target of rapamycin (mTOR), a serinethreonine kinase, plays an important role in regulation of extensive cellular activities in multiple systems, including the immune system. It mediates its effects by forming 2 distinct complexes, mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2). The demonstration of activation of mTOR activities in malignant cells led to the use of rapamycin (RAPA) and its analogs (rapalogs) in cancer therapies. However, the overall anti-cancer efficacy of rapalogs is not satisfactory with one of the major reasons being that rapalogs mainly inhibit mTORC1 activities. Thus, adenosine triphosphate-competitive mTOR inhibitors (TORKinibs), which suppress both mTORC1 and mTORC2, have been developed to overcome the shortcoming and have been shown to mediate more potent antitumor effects in preclinical studies. These findings raise the question of whether immunosuppressive effects mediated by the TORKinibs are superior to those by rapalogs. Indeed, published results do support this notion. Conditional deletion of mTOR in T cells or pharmacological inhibition of both mTORC1 and mTORC2 promoted induction of Foxp3 antigen-induced regulatory T cells. Deletion of mTOR or ablation of mTORC2 activities in B cells were shown to impair the survival of B cells and antibody responses. These data suggest that in the absence of both mTORC1 and mTORC2 or when they are both functionally suppressed, the outcome of immune responses will favor tolerance rather immunity. However, currently, how TORKinibs impact immune cells and immune responses, especially in the setting of transplantation, has remained largely unclear. In this issue, Fantus et al presented intriguing results of their study to comprehensively investigate the impacts of a TORKinib, AZD2014 that has been in clinical trial for antitumor therapy, on resting immune cell populations and on alloantigen-induced Tand B cell responses. The inclusion of RAPA as the control in this study made it possible to compare the effects of these 2 drugs side-by-side, which