Down-regulating cyclin-dependent kinase 9 of alloreactive CD4+ T cells prolongs allograft survival.
CDK9 (Cyclin-dependent kinase 9)/Cyclin T1/RNA polymerase II pathway has been demonstrated to promote the development of several inflammatory diseases, such as arthritis or atherosclerosis, however, its roles in allotransplantation rejection have not been addressed. Here, we found that CDK9/Cyclin T1 were apparently up-regulated in the allogeneic group, which was positively correlated with allograft damage. CDK9 was inhibited obviously in naive splenic CD4+ T cells treated 6 h with 3 μM PHA767491 (a CDK9 inhibitor), and adoptive transfer of these CD4+ T cells into allografted SCID mice resulted in prolonged survival compared with the group without PHA767491 pretreated. Decelerated rejection was correlated with enhanced IL-4 and IL-10 production and with decreased IFN-γ production by alloreactive T cells. More interestingly, we found that CDK942, not CDK955,was high expressed in allorejection group, which could be prominently dampened with PHA767491 treatment. The expression of CDK942 was consistent with its downstream molecule RNA polymerase II. Altogether, our findings revealed the crucial role of CDK9/Cyclin T1/Pol II pathway in promoting allorejection at multiple levels and may provide a new approach for transplantation tolerance induction through targeting CDK9.
Laboratory of Experimental Teratology, Ministry of Education and Institute of Experimental Nuclear Medicine, School of Medicine, Shandong University, Jinan, Shandong, China.
Yang
Y
Zhan
Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education and Chinese Ministry of Health, Department of Cardiology, Qilu Hospital, Shandong University, Jinan, Shandong, China.
Yeming
Y
Han
Laboratory of Experimental Teratology, Ministry of Education and Institute of Experimental Nuclear Medicine, School of Medicine, Shandong University, Jinan, Shandong, China.
Hukui
H
Sun
Laboratory of Experimental Teratology, Ministry of Education and Institute of Experimental Nuclear Medicine, School of Medicine, Shandong University, Jinan, Shandong, China.
Ting
T
Liang
Laboratory of Experimental Teratology, Ministry of Education and Institute of Experimental Nuclear Medicine, School of Medicine, Shandong University, Jinan, Shandong, China.
Chao
C
Zhang
Laboratory of Experimental Teratology, Ministry of Education and Institute of Experimental Nuclear Medicine, School of Medicine, Shandong University, Jinan, Shandong, China.
Jing
J
Song
Laboratory of Experimental Teratology, Ministry of Education and Institute of Experimental Nuclear Medicine, School of Medicine, Shandong University, Jinan, Shandong, China.
Guihua
G
Hou
D064591:Allografts; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D042863:Cyclin-Dependent Kinase 9 / Q000276:immunology*; D015536:Down-Regulation; D005260:Female; D006085:Graft Survival / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D016038:Skin Transplantation; D023001:Transplantation Tolerance / Q000276:immunology*; D014184:Transplantation, Homologous
C467972:Cdk9 protein, mouse; D042863:Cyclin-Dependent Kinase 9
CD4+ T cell; CDK9; Immune response; Immunity; Immunology and Microbiology Section; allorejection; cytokines; tolerance