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Sofi MH, Heinrichs J, Dany M, et al. Ceramide synthesis regulates T cell activity and GVHD development. JCI Insight. 2017;2(10)doi: 10.1172/jci.insight.91701.
Sofi, M. H., Heinrichs, J., Dany, M., Nguyen, H., Dai, M., Bastian, D., Schutt, S., Wu, Y., Daenthanasanmak, A., Gencer, S., Zivkovic, A., Szulc, Z., Stark, H., Liu, C., Chang, Y. J., Ogretmen, B., & Yu, X. Z. (2017). Ceramide synthesis regulates T cell activity and GVHD development. JCI insight, 2(10), . https://doi.org/10.1172/jci.insight.91701
Sofi, M Hanief, et al. "Ceramide synthesis regulates T cell activity and GVHD development." JCI insight vol. 2,10 (2017). doi: https://doi.org/10.1172/jci.insight.91701
Sofi MH, Heinrichs J, Dany M, Nguyen H, Dai M, Bastian D, Schutt S, Wu Y, Daenthanasanmak A, Gencer S, Zivkovic A, Szulc Z, Stark H, Liu C, Chang YJ, Ogretmen B, Yu XZ. Ceramide synthesis regulates T cell activity and GVHD development. JCI Insight. 2017 May 18;2(10). doi: 10.1172/jci.insight.91701. eCollection 2017 May 18. PMID: 28515365; PMCID: PMC5436544.
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JCI Insight. 2017 May 18;2(10). doi: 10.1172/jci.insight.91701. eCollection 2017 May 18.

Ceramide synthesis regulates T cell activity and GVHD development.

JCI insight

M Hanief Sofi, Jessica Heinrichs, Mohammed Dany, Hung Nguyen, Min Dai, David Bastian, Steven Schutt, Yongxia Wu, Anusara Daenthanasanmak, Salih Gencer, Aleksandra Zivkovic, Zdzislaw Szulc, Holger Stark, Chen Liu, Ying-Jun Chang, Besim Ogretmen, Xue-Zhong Yu

Affiliations

  1. Department of Microbiology and Immunology and.
  2. Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, South Carolina, USA.
  3. Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Duesseldorf, Germany.
  4. Department of Pathology and Laboratory Medicine, Rutgers-Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA.
  5. Peking University People's Hospital and Institute of Hematology, Beijing, China.

PMID: 28515365 PMCID: PMC5436544 DOI: 10.1172/jci.insight.91701

Abstract

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.

Keywords: Immunology; Transplantation

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