Adenovirus-specific CD4+ T cell clones recognizing endogenous antigen inhibit viral replication in vitro through cognate interaction.
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.
Heemskerk
Bianca
B
Department of Pediatrics, Leiden University Medical Center, 2300 RC Leiden, The Netherlands.
van Vreeswijk
Tamara
T
Veltrop-Duits
Louise A
LA
Sombroek
Claudia C
CC
Franken
Kees
K
Verhoosel
Renate M
RM
Hiemstra
Pieter S
PS
van Leeuwen
Daphne
D
Ressing
Maaike E
ME
Toes
René E M
RE
van Tol
Maarten J D
MJ
Schilham
Marco W
MW
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*
D000956:Antigens, Viral; D036022:Capsid Proteins; D000949:Histocompatibility Antigens Class II; C018315:hexon capsid protein, Adenovirus