Membrane‐bound CD95 ligand modulates CD19‐mediated B cell receptor signaling and EBV activation

Post‐transplant lymphoproliferative disorders (PTLDs) are associated with Epstein‐Barr virus (EBV) infection in transplant recipients. Most of lymphoblastoid cell lines (LCLs) derived from EBV‐immortalized B cells or PTLDs are sensitive to CD95‐mediated apoptosis and cytotoxic T cell (CTL) killing....

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Published inJournal of medical virology Vol. 96; no. 2; pp. e29440 - n/a
Main Authors Liu, Mu, Huang, Chenxu, Zhou, Xingchen, Jiang, Congwei, Liu, Shuai, Gao, Ying, Kuang, Linlin, Lei, Zhangmengxue, Jia, Ran, Xu, Jin, Legembre, Patrick, Liang, Xiaozhen
Format Journal Article
LanguageEnglish
Published United States Wiley Subscription Services, Inc 01.02.2024
Subjects
Apoptosis
B-cell receptor
Caspase
CD19
CD19 antigen
CD95
CD95 antigen
Clathrin
Cytotoxicity
Degradation
EBV‐PTLD
Epstein-Barr virus
FasL protein
Gene expression
Immunoproliferative diseases
Immunotherapy
Internalization
Ligands
Lymphoblastoid cell lines
Lymphocytes
Lymphocytes B
Lymphocytes T
Proteasomes
Receptors
CD95
EBV-PTLD
CD19
immunotherapy
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Summary:Post‐transplant lymphoproliferative disorders (PTLDs) are associated with Epstein‐Barr virus (EBV) infection in transplant recipients. Most of lymphoblastoid cell lines (LCLs) derived from EBV‐immortalized B cells or PTLDs are sensitive to CD95‐mediated apoptosis and cytotoxic T cell (CTL) killing. CD95 ligand (CD95L) exists as a transmembrane ligand (mCD95L) or a soluble form (sCD95L). Using recombinant mCD95L and sCD95L, we observed that sCD95L does not affect LCLs. While high expression of mCD95L in CTLs promotes apoptosis of LCLs, low expression induces clathrin‐dependent CD19 internalization, caspase‐dependent CD19 cleavage, and proteasomal/lysosomal‐dependent CD19 degradation. The CD95L/CD95‐mediated CD19 degradation impairs B cell receptor (BCR) signaling and inhibits BCR‐mediated EBV activation. Interestingly, although inhibition of the caspase activity restores CD19 expression and CD19‐mediated BCR activation, it fails to rescue BCR‐mediated EBV lytic gene expression. EBV‐specific CTLs engineered to overexpress mCD95L exhibit a stronger killing activity against LCLs. This study highlights that engineering EBV‐specific CTLs to express a higher level of mCD95L could represent an attractive therapeutic approach to improve T cell immunotherapy for PTLDs.
Bibliography:Mu Liu, Chenxu Huang, and Xingchen Zhou are contributed equally to this study.
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ISSN:0146-6615
1096-9071
DOI:10.1002/jmv.29440