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

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.

Cyclin‑dependent kinase 9 expression and its association with CD8+ T cell infiltration in microsatellite‑stable colorectal cancer

“…The present study explored the association between CDK9 expression and CD8 + T cells in the TME of MSS CRC. Our previous study demonstrated that PHA767491, a selective CDK9 inhibitor, could impair the activation and proliferation of effector T cells but preserve the function of Treg cells in a mouse inflammatory model (51). To the best of our knowledge, no study has reported that a CDK9 inhibitor could alter anti-inflammatory molecules or T cells in CRC.…”

Potent anti-leukemic activity of a specific cyclin-dependent kinase 9 inhibitor in mouse models of chronic lymphocytic leukemia

“…Altogether, the LDC526 anti-human T cell activity appeared more pronounced than the anti-CLL activity in the NSG spleen environment. This might be due to fact that activated T cells involved in an alloreactive (in the case of NSG, xenoreactive) response were shown to be especially sensitive to CDK9 inhibition [ 47 , 48 ]. This is consistent with the upregulation of CDK9 upon T cell activation [ 49 ].…”