Human MHC Class I-restricted high avidity CD4 + T cells generated by co-transfer of TCR and CD8 mediate efficient tumor rejection in vivo

Xue, Shao-An; Gao, Liquan; Ahmadi, Maryam; Ghorashian, Sara; Barros, Rafael D; Pospori, Constandina; Holler, Angelika; Wright, Graham; Thomas, Sharyn; Topp, Max; Morris, Emma C; Stauss, Hans J.

Abstract

In this study, we generated human MHC Class I-restricted CD4+ T cells specific for Epstein-Barr virus (EBV) and cytomegalovirus (CMV), two herpesviridae associated with lymphoma, nasopharyngeal carcinoma and medulloblastoma, respectively. Retroviral transfer of virus-specific, HLA-A2-restricted TCR-coding genes generated CD4+ T cells that recognized HLA-A2/peptide multimers and produced cytokines when stimulated with MHC Class II-deficient cells presenting the relevant viral peptides in the context of HLA-A2. Peptide titration revealed that CD4+ T cells had a 10-fold lower avidity than CD8+ T cells expressing the same TCR. The impaired avidity of CD4+ T cells was corrected by simultaneously transferring TCR- and CD8-coding genes. The CD8 co-receptor did not alter the cytokine signature of CD4+ T cells, which remained distinct from that of CD8+ T cells. Using the xenogeneic NOD/SCID mouse model, we demonstrated that human CD4+ T cells expressing a specific TCR and CD8 can confer efficient protection against the growth of tumors expressing the EBV or CMV antigens recognized by the TCR. In summary, we describe a robust approach for generating therapeutic CD4+ T cells capable of providing MHC Class I-restricted immunity against MHC Class II-negative tumors in vivo.

Citation

Xue, S., Gao, L., Ahmadi, M., Ghorashian, S., Barros, R. D., Pospori, C., …Stauss, H. J. (2013). Human MHC Class I-restricted high avidity CD4 + T cells generated by co-transfer of TCR and CD8 mediate efficient tumor rejection in vivo. OncoImmunology, 2(1), Article e22590. https://doi.org/10.4161/onci.22590

• Journal Article Type: Article
• Acceptance Date: Jan 1, 2013
• Online Publication Date: Oct 27, 2014
• Publication Date: 2013-01
• Deposit Date: Aug 1, 2016
• Publicly Available Date: Jun 28, 2023
• Journal: OncoImmunology
• Print ISSN: 2162-4011
• Electronic ISSN: 2162-402X
• Publisher: Taylor & Francis
• Peer Reviewed: Peer Reviewed
• Volume: 2
• Issue: 1
• Article Number: e22590
• DOI: https://doi.org/10.4161/onci.22590
• Keywords: CMV, EBV, TCR gene transfer, antitumor therapy, high avidity CD4 T cells, virus associated cancer
• Public URL: http://researchrepository.napier.ac.uk/Output/320454
• Additional Information: This study was supported by grants from Leukaemia and Lymphoma Research, Experimental Cancer Medicine Centre, ATTACK EU Consortium, MRC Clinical Training Fellowship, MRC/UCL Virology Centre and MRC-DPFS. We would like to thank Dr. P.H. Tan for his kind help with some of the intracellular cytokine staining experiments.