Ceramide synthesis regulates T cell activity and GVHD development

JCI Insight
M Hanief SofiXue-Zhong Yu

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 inhibito...Continue Reading

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Citations

Feb 27, 2018·Frontiers in Immunology·Hung D NguyenXue-Zhong Yu
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May 3, 2019·The Journal of Clinical Investigation·M Hanief SofiXue-Zhong Yu
Mar 24, 2020·Cell Research·Jordy SaraviaHongbo Chi
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Apr 18, 2021·The International Journal of Biochemistry & Cell Biology·Salih KucukClaudio Mauro
Aug 7, 2021·The Journal of Nutritional Biochemistry·Keri BarronNatalia Krupenko

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Methods Mentioned

BETA
SMase
flow cytometry
X-Ray

Software Mentioned

Living Image
FACSDiva

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