Sofi M Hanief, Heinrichs Jessica, Dany Mohammed, Nguyen Hung, Dai Min, Bastian David, Schutt Steven, Wu Yongxia, Daenthanasanmak Anusara, Gencer Salih, Zivkovic Aleksandra, Szulc Zdzislaw, Stark Holger, Liu Chen, Chang Ying-Jun, Ogretmen Besim, Yu Xue-Zhong
Department of Microbiology and Immunology and.
Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina, USA.
JCI Insight. 2017 May 18;2(10). doi: 10.1172/jci.insight.91701.
Allogeneic hematopoietic cell transplantation (allo-HCT) is an effective immunotherapy for a variety of hematologic malignances, yet its efficacy is impeded by the development of graft-versus-host disease (GVHD). GVHD is characterized by activation, expansion, cytokine production, and migration of alloreactive donor T cells. Hence, strategies to limit GVHD are highly desirable. Ceramides are known to contribute to inflammation and autoimmunity. However, their involvement in T-cell responses to alloantigens is undefined. In the current study, we specifically characterized the role of ceramide synthase 6 (CerS6) after allo-HCT using genetic and pharmacologic approaches. We found that CerS6 was required for optimal T cell activation, proliferation, and cytokine production in response to alloantigen and for subsequent induction of GVHD. However, CerS6 was partially dispensable for the T cell-mediated antileukemia effect. At the molecular level, CerS6 was required for efficient TCR signal transduction, including tyrosine phosphorylation, ZAP-70 activation, and PKCθ/TCR colocalization. Impaired generation of C16-ceramide was responsible for diminished allogeneic T cell responses. Furthermore, targeting CerS6 using a specific inhibitor significantly reduced T cell activation in mouse and human T cells in vitro. Our study provides a rationale for targeting CerS6 to control GVHD, which would enhance the efficacy of allo-HCT as an immunotherapy for hematologic malignancies in the clinic.
异基因造血细胞移植（allo-HCT）是治疗多种血液系统恶性肿瘤的一种有效免疫疗法，但其疗效因移植物抗宿主病（GVHD）的发生而受到阻碍。GVHD的特征是同种异体反应性供体T细胞的激活、扩增、细胞因子产生和迁移。因此，非常需要限制GVHD的策略。已知神经酰胺会导致炎症和自身免疫。然而，它们在T细胞对同种异体抗原的反应中的作用尚不清楚。在本研究中，我们使用基因和药理学方法具体表征了allo-HCT后神经酰胺合酶6（CerS6）的作用。我们发现，CerS6是同种异体抗原刺激后T细胞最佳激活、增殖和细胞因子产生以及随后诱导GVHD所必需的。然而，CerS6对于T细胞介导的抗白血病作用部分是可有可无的。在分子水平上，CerS6是有效TCR信号转导所必需的，包括酪氨酸磷酸化、ZAP-70激活和PKCθ/TCR共定位。C16-神经酰胺生成受损导致同种异体T细胞反应减弱。此外，使用特异性抑制剂靶向CerS6可在体外显著降低小鼠和人T细胞的激活。我们的研究为靶向CerS6以控制GVHD提供了理论依据，这将提高allo-HCT作为血液系统恶性肿瘤临床免疫疗法的疗效。
