title: CD28 co-stimulation via tumour-specific chimaeric receptors induces an incomplete activation response in Epstein-Barr virus-specific effector memory T cells.
abstract: Expression of tumour antigen-specific chimaeric receptors in T lymphocytes can redirect their effector functions towards tumour cells. Integration of the signalling domains of the co-stimulatory molecule CD28 into chRec enhances antigen-specific proliferation of polyclonal human T cell populations. While CD28 plays an essential role in the priming of naive CD4(+) T cells, its contribution to effector memory T cell responses is controversial. We compared the function of the chRec with and without the CD28 co-stimulatory domain, expressing it in peripheral blood T cells or Epstein-Barr virus (EBV)-specific T cell lines. The chimaeric T cell receptors contain an extracellular single-chain antibody domain, to give specificity against the tumour ganglioside antigen G(D2). The transduced cytotoxic T lymphocytes (CTL) maintained their specificity for autologous EBV targets and their capacity to proliferate after stimulation with EBV-infected B cells. Intracellular cytokine staining demonstrated efficient and comparable antigen-specific interferon (IFN)-gamma secretion by CTL following engagement of both the native and the chimaeric receptor, independent of chimaeric CD28 signalling. Furthermore, tumour targets were lysed in an antigen-specific manner by both chRec. However, while antigen engagement by CD28 zeta chRec efficiently induced expansion of polyclonal peripheral blood lymphocytes in an antigen-dependent manner, CD28 signalling did not induce proliferation of EBV-CTL in response to antigen-expressing tumour cells. Thus, the co-stimulatory requirement for the efficient activation response of antigen-specific memory cells cannot be mimicked simply by combining CD28 and zeta signalling. The full potential of this highly cytolytic T cell population for adoptive immunotherapy of cancer requires further exploration of their co-stimulatory requirements.
authors.affiliation: University Children's Hospital Münster, Department of Paediatric Haematology and Oncology, Münster, Germany.
authors.forename: B
authors.initials: B
authors.lastname: Altvater
authors.forename: S
authors.initials: S
authors.lastname: Pscherer
authors.forename: S
authors.initials: S
authors.lastname: Landmeier
authors.forename: V
authors.initials: V
authors.lastname: Niggemeier
authors.forename: H
authors.initials: H
authors.lastname: Juergens
authors.forename: J
authors.initials: J
authors.lastname: Vormoor
authors.forename: C
authors.initials: C
authors.lastname: Rossig
mesh_terms: D000951:Antigens, Neoplasm / Q000276:immunology; D018106:CD28 Antigens / Q000276:immunology*; D049109:Cell Proliferation; D003602:Cytotoxicity, Immunologic / Q000276:immunology; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D004854:Herpesvirus 4, Human / Q000276:immunology*; D006801:Humans; D007156:Immunologic Memory / Q000276:immunology*; D016130:Immunophenotyping; D007167:Immunotherapy / Q000379:methods; D008213:Lymphocyte Activation / Q000276:immunology*; D008565:Membrane Proteins / Q000235:genetics / Q000276:immunology; D009369:Neoplasms / Q000276:immunology*; D011948:Receptors, Antigen, T-Cell / Q000235:genetics / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology; D014161:Transduction, Genetic; D014407:Tumor Cells, Cultured
chemical_list: D000951:Antigens, Neoplasm; D018106:CD28 Antigens; D018984:Epitopes, T-Lymphocyte; D008565:Membrane Proteins; D011948:Receptors, Antigen, T-Cell; C054979:antigen T cell receptor, zeta chain