title: Non-cognate bystander cytolysis by clonal epitope-specific CTL lines through CD28-CD80 interaction inhibits antibody production: A potential caveat to CD8 T-cell immunotherapy.
abstract: Adoptive transfer of virus epitope-specific CD8 T cells is an immunotherapy option to control cytomegalovirus (CMV) infection and prevent CMV organ disease in immunocompromised solid organ transplantation (SOT) and hematopoietic cell transplantation (HCT) recipients. The therapy aims at an early, selective recognition and cytolysis of infected cells for preventing viral spread in tissues with no adverse immunopathogenic side-effects by attack of uninfected bystander cells. Here we describe that virus epitope-specific, cloned T-cell lines lyse target cells that present the cognate antigenic peptide to the TCR, but simultaneously have the potential to lyse uninfected cells expressing the CD28 ligand CD80 (B7-1). While TCR-mediated cytolysis requires co-receptor CD8 and depends on perforin, the TCR-independent and viral epitope-independent cytolysis through CD28-CD80 signaling does not require CD8 on the effector cells and is perforin-independent. Importantly, this non-cognate cytolysis pathway leads to bystander cytolysis of CD80-expressing B-cell blasts and thereby inhibits pan-specific antibody production.
authors.affiliation: Institute for Virology and Research Center for Immunotherapy (FZI), University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany.
authors.forename: Rafaela
authors.initials: R
authors.lastname: Holtappels
authors.affiliation: Institute for Virology and Research Center for Immunotherapy (FZI), University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Podlech
authors.affiliation: Institute for Virology and Research Center for Immunotherapy (FZI), University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany.
authors.forename: Niels A W
authors.initials: NA
authors.lastname: Lemmermann
authors.affiliation: Institute for Immunology and Research Center for Immunotherapy (FZI), University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany.
authors.forename: Edgar
authors.initials: E
authors.lastname: Schmitt
authors.affiliation: Institute for Virology and Research Center for Immunotherapy (FZI), University Medical Center of the Johannes Gutenberg-University Mainz, 55131 Mainz, Germany. Electronic address: Matthias.Reddehase@uni-mainz.de.
authors.forename: Matthias J
authors.initials: MJ
authors.lastname: Reddehase
mesh_terms: D000818:Animals; D000917:Antibody Formation; D001402:B-Lymphocytes / Q000276:immunology*; D018122:B7-1 Antigen / Q000378:metabolism; D024201:Bystander Effect; D018106:CD28 Antigens / Q000378:metabolism; D002999:Clone Cells; D003587:Cytomegalovirus / Q000276:immunology*; D003586:Cytomegalovirus Infections / Q000276:immunology*; D003602:Cytotoxicity, Immunologic; D018984:Epitopes, T-Lymphocyte / Q000378:metabolism; D018380:Hematopoietic Stem Cell Transplantation; D016219:Immunotherapy, Adoptive / Q000009:adverse effects / Q000379:methods*; D051379:Mice; D016377:Organ Transplantation; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*
chemical_list: D018122:B7-1 Antigen; D018106:CD28 Antigens; D018984:Epitopes, T-Lymphocyte
keywords: Antibody; B-cell blasts; B7-1 (CD80); Bystander cytolysis; CD28–CD80 interaction; CD8 T cells; Cytomegalovirus; Immunopathogenesis; Immunotherapy; Transplantation