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

摘要

In this study, we generated human MHC Class I-restricted CD4(+) T cells specific for Epstein-Barr virus (EBV) and cytomegalovirus (CMV), two herpesviridaeassociated with lymphoma, nasopharyngeal carcinoma and medulloblastoma,respectively. Retroviral transfer of virus-specific, HLA-A2-restricted TCR-codinggenes generated CD4(+) T cells that recognized HLA-A2/peptide multimers andproduced cytokines when stimulated with MHC Class II-deficient cells presentingthe 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 expressingthe same TCR. The impaired avidity of CD4(+) T cells was corrected bysimultaneously transferring TCR- and CD8-coding genes. The CD8 co-receptor didnot alter the cytokine signature of CD4(+) T cells, which remained distinct from that of CD8(+) T cells. Using the xenogeneic NOD/SCID mouse model, wedemonstrated that human CD4(+) T cells expressing a specific TCR and CD8 canconfer efficient protection against the growth of tumors expressing the EBV orCMV antigens recognized by the TCR. In summary, we describe a robust approach forgenerating therapeutic CD4(+) T cells capable of providing MHC Class I-restrictedimmunity against MHC Class II-negative tumors in vivo.