Ceramide synthesis regulates T cell activity and GVHD development
| Autor: | Mohammed Dany, Ying-Jun Chang, Hung Nguyen, Xue-Zhong Yu, Holger Stark, David Bastian, Yongxia Wu, Salih Gencer, M. Hanief Sofi, Min Dai, Steven Schutt, Zdzislaw M. Szulc, Anusara Daenthanasanmak, Chen Liu, Jessica Heinrichs, Aleksandra Zivkovic, Besim Ogretmen |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
business.industry medicine.medical_treatment T cell T-cell receptor chemical and pharmacologic phenomena Tyrosine phosphorylation General Medicine Immunotherapy Transplantation 03 medical and health sciences chemistry.chemical_compound surgical procedures operative 030104 developmental biology Cytokine medicine.anatomical_structure chemistry Cancer research Medicine Signal transduction business Ceramide synthase Research Article |
| Zdroj: | JCI Insight. 2 |
| ISSN: | 2379-3708 |
| DOI: | 10.1172/jci.insight.91701 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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