title: CD8 T cell tolerance to a tumor-associated self-antigen is reversed by CD4 T cells engineered to express the same T cell receptor.
abstract: Ag receptors used for cancer immunotherapy are often directed against tumor-associated Ags also expressed in normal tissues. Targeting of such Ags can result in unwanted autoimmune attack of normal tissues or induction of tolerance in therapeutic T cells. We used a murine model to study the phenotype and function of T cells redirected against the murine double minute protein 2 (MDM2), a tumor-associated Ag that shows low expression in many normal tissues. Transfer of MDM2-TCR-engineered T cells into bone marrow chimeric mice revealed that Ag recognition in hematopoietic tissues maintained T cell function, whereas presentation of MDM2 in nonhematopoietic tissues caused reduced effector function. TCR-engineered CD8(+) T cells underwent rapid turnover, downmodulated CD8 expression, and lost cytotoxic function. We found that MDM2-TCR-engineered CD4(+) T cells provided help and restored cytotoxic function of CD8(+) T cells bearing the same TCR. Although the introduction of the CD8 coreceptor enhanced the ability of CD4(+) T cells to recognize MDM2 in vitro, the improved self-antigen recognition abolished their ability to provide helper function in vivo. The data indicate that the same class I-restricted TCR responsible for Ag recognition and tolerance induction in CD8(+) T cells can, in the absence of the CD8 coreceptor, elicit CD4 T cell help and partially reverse tolerance. Thus MHC class I-restricted CD4(+) T cells may enhance the efficacy of therapeutic TCR-engineered CD8(+) T cells and can be readily generated with the same TCR.
authors.affiliation: Institute of Immunity and Transplantation, University College London, Royal Free Hospital, London NW3 2PF, United Kingdom; Transplantation Immunology Group, Department of Haematology, Division of Cancer Studies, University College London, London NW3 2PF, United Kingdom; and.
authors.forename: Sara
authors.initials: S
authors.lastname: Ghorashian
authors.affiliation: Institute of Immunity and Transplantation, University College London, Royal Free Hospital, London NW3 2PF, United Kingdom; Transplantation Immunology Group, Department of Haematology, Division of Cancer Studies, University College London, London NW3 2PF, United Kingdom; and.
authors.forename: Pedro
authors.initials: P
authors.lastname: Veliça
authors.affiliation: Institute of Immunity and Transplantation, University College London, Royal Free Hospital, London NW3 2PF, United Kingdom;
authors.forename: Ignatius
authors.initials: I
authors.lastname: Chua
authors.affiliation: Institute of Immunity and Transplantation, University College London, Royal Free Hospital, London NW3 2PF, United Kingdom;
authors.forename: Anne-Marie
authors.initials: AM
authors.lastname: McNicol
authors.affiliation: Transplantation Immunology Group, Department of Haematology, Division of Cancer Studies, University College London, London NW3 2PF, United Kingdom; and.
authors.forename: Ben
authors.initials: B
authors.lastname: Carpenter
authors.affiliation: Institute of Immunity and Transplantation, University College London, Royal Free Hospital, London NW3 2PF, United Kingdom;
authors.forename: Angelika
authors.initials: A
authors.lastname: Holler
authors.affiliation: Institute of Immunity and Transplantation, University College London, Royal Free Hospital, London NW3 2PF, United Kingdom;
authors.forename: Emma
authors.initials: E
authors.lastname: Nicholson
authors.affiliation: Institute of Immunity and Transplantation, University College London, Royal Free Hospital, London NW3 2PF, United Kingdom;
authors.forename: Maryam
authors.initials: M
authors.lastname: Ahmadi
authors.affiliation: Institute of Immunity and Transplantation, University College London, Royal Free Hospital, London NW3 2PF, United Kingdom;
authors.forename: Mathias
authors.initials: M
authors.lastname: Zech
authors.affiliation: Institute of Immunity and Transplantation, University College London, Royal Free Hospital, London NW3 2PF, United Kingdom;
authors.forename: Shao-An
authors.initials: SA
authors.lastname: Xue
authors.affiliation: Institute of Biology, Humboldt University Berlin and Max Delbrück Center for Molecular Medicine, 13125 Berlin, Germany.
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Uckert
authors.affiliation: Institute of Immunity and Transplantation, University College London, Royal Free Hospital, London NW3 2PF, United Kingdom;
authors.forename: Emma
authors.initials: E
authors.lastname: Morris
authors.affiliation: Transplantation Immunology Group, Department of Haematology, Division of Cancer Studies, University College London, London NW3 2PF, United Kingdom; and.
authors.forename: Ronjon
authors.initials: R
authors.lastname: Chakraverty
authors.affiliation: Institute of Immunity and Transplantation, University College London, Royal Free Hospital, London NW3 2PF, United Kingdom; h.stauss@ucl.ac.uk.
authors.forename: Hans J
authors.initials: HJ
authors.lastname: Stauss
mesh_terms: D019264:Adoptive Transfer; D000818:Animals; D000951:Antigens, Neoplasm / Q000276:immunology*; D001324:Autoantigens / Q000276:immunology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000378:metabolism*; D002450:Cell Communication; D003602:Cytotoxicity, Immunologic; D015870:Gene Expression; D007108:Immune Tolerance; D016130:Immunophenotyping; D051379:Mice; D008822:Mice, Transgenic; D010641:Phenotype; D051736:Proto-Oncogene Proteins c-mdm2 / Q000235:genetics; D011948:Receptors, Antigen, T-Cell / Q000235:genetics* / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism; D014161:Transduction, Genetic
chemical_list: D000951:Antigens, Neoplasm; D001324:Autoantigens; D011948:Receptors, Antigen, T-Cell; D011993:Recombinant Fusion Proteins; D051736:Proto-Oncogene Proteins c-mdm2