title: Human CD4+ T Helper Cell Responses after Tick-Borne Encephalitis Vaccination and Infection.
abstract: Tick-borne encephalitis virus (TBEV) is a human-pathogenic flavivirus that is endemic in large parts of Europe and Asia and causes severe neuroinvasive illness. A formalin-inactivated vaccine induces strong neutralizing antibody responses and confers protection from TBE disease. CD4+ T cell responses are essential for neutralizing antibody production, but data on the functionalities of TBEV-specific CD4+ T cells in response to vaccination or infection are lacking. This study provides a comprehensive analysis of the cytokine patterns of CD4+ T cell responses in 20 humans after TBE vaccination in comparison to those in 18 patients with TBEV infection. Specifically, Th1-specific cytokines (IFN-γ, IL-2, TNF-α), CD40 ligand and the Th1 lineage-specifying transcription factor Tbet were determined upon stimulation with peptides covering the TBEV structural proteins contained in the vaccine (C-capsid, prM/M-membrane and E-envelope). We show that TBEV-specific CD4+ T cell responses are polyfunctional, but the cytokine patterns after vaccination differed from those after infection. TBE vaccine responses were characterized by lower IFN-γ responses and high proportions of TNF-α+IL-2+ cells. In vaccine-induced responses-consistent with the reduced IFN-γ expression patterns-less than 50% of TBEV peptides were detected by IFN-γ+ cells as compared to 96% detected by IL-2+ cells, indicating that the single use of IFN-γ as a read-out strongly underestimates the magnitude and breadth of such responses. The results provide important insights into the functionalities of CD4+ T cells that coordinate vaccine responses and have direct implications for future studies that address epitope specificity and breadth of these responses.
authors.affiliation: Department of Virology, Medical University of Vienna, Vienna, Austria.
authors.forename: Judith H
authors.initials: JH
authors.lastname: Aberle
authors.affiliation: Department of Virology, Medical University of Vienna, Vienna, Austria.
authors.forename: Julia
authors.initials: J
authors.lastname: Schwaiger
authors.affiliation: Department of Virology, Medical University of Vienna, Vienna, Austria.
authors.forename: Stephan W
authors.initials: SW
authors.lastname: Aberle
authors.affiliation: Department of Virology, Medical University of Vienna, Vienna, Austria.
authors.forename: Karin
authors.initials: K
authors.lastname: Stiasny
authors.affiliation: Laboratory of Molecular Genetics, Hospital České Budĕjovice, České Budĕjovice, Czech Republic.
authors.forename: Ondrej
authors.initials: O
authors.lastname: Scheinost
authors.affiliation: Centre for Public Health, Medical University of Vienna, Vienna, Austria.
authors.forename: Michael
authors.initials: M
authors.lastname: Kundi
authors.affiliation: Department of Infectious Diseases, Hospital České Budĕjovice, České Budĕjovice, Czech Republic.
authors.forename: Vaclav
authors.initials: V
authors.lastname: Chmelik
authors.affiliation: Department of Virology, Medical University of Vienna, Vienna, Austria.
authors.forename: Franz X
authors.initials: FX
authors.lastname: Heinz
mesh_terms: D000328:Adult; D000368:Aged; D000914:Antibodies, Viral / Q000097:blood / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D019070:Cell Lineage / Q000276:immunology; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D004669:Encephalitis Viruses, Tick-Borne / Q000276:immunology / Q000472:pathogenicity; D004675:Encephalitis, Tick-Borne / Q000276:immunology* / Q000517:prevention & control / Q000821:virology; D000939:Epitopes / Q000276:immunology; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects / Q000276:immunology*; D014611:Vaccination; D014765:Viral Vaccines / Q000008:administration & dosage* / Q000276:immunology
chemical_list: D000914:Antibodies, Viral; D016207:Cytokines; D000939:Epitopes; D014765:Viral Vaccines