title: Adenovirus-specific CD4+ T cell clones recognizing endogenous antigen inhibit viral replication in vitro through cognate interaction.
abstract: Human adenovirus (HAdV) infection is a frequent and potentially severe complication following allogeneic stem cell transplantation in children. Because treatment with antiviral drugs is often ineffective, adoptive transfer of donor-derived HAdV-specific T cells able to control viral replication of HAdV of multiple serotypes may be an option for therapy. In healthy donors, predominantly HAdV-specific T cells expressing CD4 are detected. In this study, a preclinical in vitro model was used to measure the antiviral effect of HAdV-specific CD4+ T cells. CD4+ HAdV-specific T cell clones restricted by HLA class II molecules were generated and most of these clones recognized conserved peptides derived from the hexon protein. These cross-reactive T cell clones were able to control viral replication of multiple serotypes of HAdV in EBV-transformed B cells (B-LCL), melanoma cells (MJS) and primary bronchial epithelial cells through cognate interaction. The HAdV-specific CD4+ T cell clones were able to specifically lyse infected target cells using a perforin-dependent mechanism. Antigenic peptides were also presented to the CD4+ T cell clones when derived from endogenously produced hexon protein. Together, these results show that cross-reactive HAdV-specific CD4+ T cells can control replication of HAdV in vitro and provide a rationale for the use of HAdV-specific T cells in adoptive immunotherapy protocols for control of life-threatening HAdV-infections in immunocompromised patients.
authors.affiliation: Department of Pediatrics, Leiden University Medical Center, 2300 RC Leiden, The Netherlands.
authors.forename: Bianca
authors.initials: B
authors.lastname: Heemskerk
authors.forename: Tamara
authors.initials: T
authors.lastname: van Vreeswijk
authors.forename: Louise A
authors.initials: LA
authors.lastname: Veltrop-Duits
authors.forename: Claudia C
authors.initials: CC
authors.lastname: Sombroek
authors.forename: Kees
authors.initials: K
authors.lastname: Franken
authors.forename: Renate M
authors.initials: RM
authors.lastname: Verhoosel
authors.forename: Pieter S
authors.initials: PS
authors.lastname: Hiemstra
authors.forename: Daphne
authors.initials: D
authors.lastname: van Leeuwen
authors.forename: Maaike E
authors.initials: ME
authors.lastname: Ressing
authors.forename: René E M
authors.initials: RE
authors.lastname: Toes
authors.forename: Maarten J D
authors.initials: MJ
authors.lastname: van Tol
authors.forename: Marco W
authors.initials: MW
authors.lastname: Schilham
mesh_terms: D000258:Adenovirus Infections, Human / Q000628:therapy*; D000260:Adenoviruses, Human / Q000276:immunology*; D019264:Adoptive Transfer / Q000379:methods*; D000956:Antigens, Viral / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D036022:Capsid Proteins / Q000276:immunology; D002478:Cells, Cultured; D002999:Clone Cells / Q000276:immunology; D003429:Cross Reactions / Q000276:immunology; D003602:Cytotoxicity, Immunologic; D000949:Histocompatibility Antigens Class II / Q000276:immunology*; D006801:Humans; D037182:T-Cell Antigen Receptor Specificity / Q000276:immunology*; D014779:Virus Replication / Q000276:immunology*
chemical_list: D000956:Antigens, Viral; D036022:Capsid Proteins; D000949:Histocompatibility Antigens Class II; C018315:hexon capsid protein, Adenovirus