title: Human MHC Class I-restricted high avidity CD4+T cells generated by co-transfer of TCR and CD8 mediate efficient tumor rejection in vivo.
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.
authors.affiliation: Department of Immunology; University College London; Royal Free Hospital; London, United Kingdom.
authors.forename: Shao-An
authors.initials: SA
authors.lastname: Xue
authors.forename: Liquan
authors.initials: L
authors.lastname: Gao
authors.forename: Maryam
authors.initials: M
authors.lastname: Ahmadi
authors.forename: Sara
authors.initials: S
authors.lastname: Ghorashian
authors.forename: Rafael D
authors.initials: RD
authors.lastname: Barros
authors.forename: Constandina
authors.initials: C
authors.lastname: Pospori
authors.forename: Angelika
authors.initials: A
authors.lastname: Holler
authors.forename: Graham
authors.initials: G
authors.lastname: Wright
authors.forename: Sharyn
authors.initials: S
authors.lastname: Thomas
authors.forename: Max
authors.initials: M
authors.lastname: Topp
authors.forename: Emma C
authors.initials: EC
authors.lastname: Morris
authors.forename: Hans J
authors.initials: HJ
authors.lastname: Stauss
keywords: CMV; EBV; TCR gene transfer; antitumor therapy; high avidity CD4 T cells; virus associated cancer