Oncotarget

Research Papers: Immunology:

Down-regulating cyclin-dependent kinase 9 of alloreactive CD4+ T cells prolongs allograft survival

Yang Zhan, Yeming Han, Hukui Sun, Ting Liang, Chao Zhang, Jing Song and Guihua Hou _

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Oncotarget. 2016; 7:24983-24994. https://doi.org/10.18632/oncotarget.8804

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Abstract

Yang Zhan1, Yeming Han2, Hukui Sun1, Ting Liang1, Chao Zhang1, Jing Song1 and Guihua Hou1

1 Laboratory of Experimental Teratology, Ministry of Education and Institute of Experimental Nuclear Medicine, School of Medicine, Shandong University, Jinan, Shandong, China

2 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

Correspondence to:

Guihua Hou, email:

Keywords: CDK9, cytokines, allorejection, tolerance, CD4+ T cell, Immunology and Microbiology Section, Immune response, Immunity

Received: December 14, 2015 Accepted: April 06, 2016 Published: April 18, 2016

Abstract

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.


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