Dasatinib exerts an immunosuppressive effect on CD8+ T cells specific for viral and leukemia antigens.
OBJECTIVE
To investigate the inhibitory effects of dasatinib on proliferation, function, and signaling events on CD8+T cells.


METHODS
Carboxyfluorescein diacetate succinimidyl ester and 5-bromo-2-deoxyuridine were used to detect proliferation and cell cycle of CD8+T cells treated with dasatinib, respectively. Frequency and function of viral and leukemia-antigen-specific CD8+T cells from healthy donors were measured by tetramer staining and ELISPOT assay. Western blotting analysis was performed to detect T-cell receptor (TCR), nuclear factor kappa B (NF-kappaB) and Src signaling events in T cells treated with dasatinib or imatinib.


RESULTS
Dasatinib inhibited proliferation of CD8+T cells in a dose-dependent manner, which was associated with lower secretion of interferon-gamma and granzyme B, as well as with arrest of CD8+T cells in the G0/G1 phase of cell cycle. Inhibition of CD8+T cells was proven for blood samples from a patient under dasatinib medication when compared with their T-cell status without dasatinib. Western blotting confirmed that these effects were mediated through downregulation of the phosphorylation level of molecules from the TCR and the NF-kappaB signaling transduction cascade. Dasatinib proved to be more potent than imatinib on Src and TCR signaling events in Jurkat T cells.


CONCLUSIONS
Our study demonstrated that dasatinib impaired proliferation and function of CD8+T cells via TCR and NF-kappaB signaling events without inducing apoptosis. Therefore, dasatinib might alter the graft-vs-leukemia effect and the graft-vs-host disease after allogeneic stem cell transplantation sustained by CD8+T cells. Dasatinib might also be used as a novel immunosuppressant agent.
Fei
Fei
F
Department of Internal Medicine III, University of Ulm, Ulm, Germany.
Yu
Yingzhe
Y
Schmitt
Anita
A
Rojewski
Markus Thomas
MT
Chen
Baoan
B
Greiner
Jochen
J
Götz
Marlies
M
Guillaume
Philippe
P
Döhner
Hartmut
H
Bunjes
Donald
D
Schmitt
Michael
M
D000951:Antigens, Neoplasm / Q000187:drug effects / Q000276:immunology*; D000956:Antigens, Viral / Q000187:drug effects / Q000276:immunology*; D017209:Apoptosis / Q000187:drug effects; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000276:immunology*; D002455:Cell Division / Q000187:drug effects; D000069439:Dasatinib; D006801:Humans; D007165:Immunosuppression Therapy; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects / Q000276:immunology; D007959:Lymphocyte Culture Test, Mixed; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013844:Thiazoles / Q000494:pharmacology*
D000951:Antigens, Neoplasm; D000956:Antigens, Viral; D007166:Immunosuppressive Agents; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D013844:Thiazoles; D000069439:Dasatinib