Virus-specific cytotoxic CD4+ T cells for the treatment of EBV-related tumors

Merlo, Anna, Turrini, Riccardo, Bobisse, Sara, Zamarchi, Rita, Alaggio, Rita, Dolcetti, Riccardo, Mautner, Josef, Zanovello, Paola, Amadori, Alberto and Rosato, Antonio (2010) Virus-specific cytotoxic CD4+ T cells for the treatment of EBV-related tumors. Journal of Immunology, 184 10: 5895-5902. doi:10.4049/jimmunol.0902850


Author Merlo, Anna
Turrini, Riccardo
Bobisse, Sara
Zamarchi, Rita
Alaggio, Rita
Dolcetti, Riccardo
Mautner, Josef
Zanovello, Paola
Amadori, Alberto
Rosato, Antonio
Title Virus-specific cytotoxic CD4+ T cells for the treatment of EBV-related tumors
Formatted title
Virus-specific cytotoxic CD4+ T cells for the treatment of EBV-related tumors
Journal name Journal of Immunology   Check publisher's open access policy
ISSN 0022-1767
1550-6606
Publication date 2010-05-15
Sub-type Article (original research)
DOI 10.4049/jimmunol.0902850
Open Access Status Not yet assessed
Volume 184
Issue 10
Start page 5895
End page 5902
Total pages 8
Place of publication Bethesda, MD, United States
Publisher American Association of Immunologists
Language eng
Formatted abstract
Although adoptive immunotherapy with CD8+ CTL is providing clinically relevant results against EBV-driven malignancies, the effector role of CD4+ T cells has been poorly investigated. We addressed this issue in a lymphoblastoid cell line-induced mouse model of posttransplant lymphoproliferative disease (PTLD) by comparing the therapeutic efficacy of EBV-specific CD4+ and CD8+ T cell lines upon adoptive transfer. CD4+ T cells disclosed a long-lasting and stronger proliferative potential than CD8+ T cells, had a similar activation and differentiation marker profile, efficiently killed their targets in a MHC class II-restricted manner, and displayed a lytic machinery comparable to that of cognate CD8+ T cells. A detailed analysis of Ag specificity revealed that CD4+ T cells potentially target EBV early lytic cycle proteins. Nonetheless, when assessed for the relative therapeutic impact after in vivo transfer, CD4+ T cells showed a reduced activity compared with the CD8+ CTL counterpart. This feature was apparently due to a strong and selective downmodulation of MHC class II expression on the tumor cells surface, a phenomenon that could be reverted by the demethylating agent 5-aza-2′-deoxycytidine, thus leading to restoration of lymphoblastoid cell line recognition and killing by CD4+ T cells, as well as to a more pronounced therapeutic activity. Conversely, immunohistochemical analysis disclosed that HLA-II expression is fully retained in human PTLD samples. Our data indicate that EBV-specific cytotoxic CD4+ T cells are therapeutic in mice bearing PTLD-like tumors, even in the absence of CD8+ T cells. These findings pave the way to use cultures of pure CD4+ T cells in immunotherapeutic approaches for EBV-related malignancies. 
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status Non-UQ

Document type: Journal Article
Sub-type: Article (original research)
Collection: UQ Diamantina Institute Publications
 
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