Journal
ONCOIMMUNOLOGY
Volume 2, Issue 1, Pages -Publisher
TAYLOR & FRANCIS INC
DOI: 10.4161/onci.22590
Keywords
high avidity CD4 T cells; TCR gene transfer; virus associated cancer; EBV; CMV; antitumor therapy
Categories
Funding
- Leukaemia and Lymphoma Research
- ATTACK EU Consortium
- MRC Clinical Training Fellowship
- MRC/UCL Virology Centre
- MRC-DPFS
- Experimental Cancer Medicine Centre
- Medical Research Council [G0900950, G9721629B, G0501446, G0700568, G0902209, G0900950B, G9721629] Funding Source: researchfish
- Versus Arthritis [19225] Funding Source: researchfish
- MRC [G0700568, G9721629, G0900950, G0902209, G0501446] Funding Source: UKRI
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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/SC ID 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.
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