title: CD3 limits the efficacy of TCR gene therapy in vivo.
abstract: The function of T-cell receptor (TCR) gene modified T cells is dependent on efficient surface expression of the introduced TCR α/β heterodimer. We tested whether endogenous CD3 chains are rate-limiting for TCR expression and antigen-specific T-cell function. We show that co-transfer of CD3 and TCR genes into primary murine T cells enhanced TCR expression and antigen-specific T-cell function in vitro. Peptide titration experiments showed that T cells expressing introduced CD3 and TCR genes recognized lower concentration of antigen than T cells expressing TCR only. In vivo imaging revealed that TCR+CD3 gene modified T cells infiltrated tumors faster and in larger numbers, which resulted in more rapid tumor elimination compared with T cells modified by TCR only. After tumor clearance, TCR+CD3 engineered T cells persisted in larger numbers than TCR-only T cells and mounted a more effective memory response when rechallenged with antigen. The data demonstrate that provision of additional CD3 molecules is an effective strategy to enhance the avidity, anti-tumor activity and functional memory formation of TCR gene modified T cells in vivo.
authors.affiliation: Department of Immunology, University College London (UCL), Royal Free Hospital, London, UK.
authors.forename: Maryam
authors.initials: M
authors.lastname: Ahmadi
authors.forename: Judith W
authors.initials: JW
authors.lastname: King
authors.forename: Shao-An
authors.initials: SA
authors.lastname: Xue
authors.forename: Cécile
authors.initials: C
authors.lastname: Voisine
authors.forename: Angelika
authors.initials: A
authors.lastname: Holler
authors.forename: Graham P
authors.initials: GP
authors.lastname: Wright
authors.forename: Jonathan
authors.initials: J
authors.lastname: Waxman
authors.forename: Emma
authors.initials: E
authors.lastname: Morris
authors.forename: Hans J
authors.initials: HJ
authors.lastname: Stauss
mesh_terms: D000818:Animals; D017252:CD3 Complex / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D002478:Cells, Cultured; D015536:Down-Regulation; D005260:Female; D019672:Genes, T-Cell Receptor / Q000235:genetics*; D015316:Genetic Therapy / Q000379:methods; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D006801:Humans; D016399:Lymphoma, T-Cell / Q000235:genetics / Q000473:pathology / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D016896:Treatment Outcome
chemical_list: D017252:CD3 Complex; D011993:Recombinant Fusion Proteins; D049452:Green Fluorescent Proteins