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Effect of mTORC 1/ mTORC 2 inhibition on T cell function: potential role in graft‐ versus ‐host disease control
Author(s) -
HerreroSánchez Ma Carmen,
RodríguezSerrano Concepción,
Almeida Julia,
SanSegundo Laura,
Inogés Susana,
SantosBriz Ángel,
GarcíaBriñón Jesús,
SanMiguel Jesús F.,
Del Cañizo Consuelo,
Blanco Belén
Publication year - 2016
Publication title -
british journal of haematology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.907
H-Index - 186
eISSN - 1365-2141
pISSN - 0007-1048
DOI - 10.1111/bjh.13984
Subject(s) - mtorc1 , pi3k/akt/mtor pathway , mtorc2 , t cell , transplantation , sirolimus , mechanistic target of rapamycin , graft versus host disease , cancer research , immunology , immune system , medicine , biology , microbiology and biotechnology , signal transduction
Summary The mechanistic target of rapamycin ( mTOR ) pathway is crucial for the activation and function of T cells, which play an essential role in the development of graft‐ versus ‐host disease (Gv HD ). Despite its partial ability to block mTOR pathway, the mTORC 1 inhibitor rapamycin has shown encouraging results in the control of Gv HD . Therefore, we considered that simultaneous targeting of both mTORC 1 and mTORC 2 complexes could exert a more potent inhibition of T cell activation and, thus, could have utility in Gv HD control. To assess this assumption, we have used the dual mTORC 1/ mTORC 2 inhibitors CC 214‐1 and CC 214‐2. In vitro studies confirmed the superior ability of CC 214‐1 versus rapamycin to block mTORC 1 and mTORC 2 activity and to reduce T cell proliferation. Both drugs induced a similar decrease in Th1/Th2 cytokine secretion, but CC 214‐1 was more efficient in inhibiting naïve T cell activation and the expression of T‐cell activation markers. In addition, CC 214‐1 induced specific tolerance against alloantigens, while preserving anti‐cytomegalovirus response. Finally, in a mouse model of Gv HD , the administration of CC 214‐2 significantly improved mice survival and decreased Gv HD ‐induced damages. In conclusion, the current study shows, for the first time, the immunosuppressive ability of CC 214‐1 on T lymphocytes and illustrates the role of CC 214‐2 in the allogeneic transplantation setting as a possible Gv HD prophylaxis agent.