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.

Tick-Borne Encephalitis Virus Nonstructural Protein NS5 Induces RANTES Expression Dependent on the RNA-Dependent RNA Polymerase Activity

“…For neuroinvasive flaviviruses, T cell-mediated immunity is important for protection from disease and for viral clearance from the CNS (57)(58)(59). It is known that TBEV-specific CD4 + T cells recruited by RANTES are polyfunctional (60). During the early stage of TBE in humans, the majority of cells recruited to the CNS are T lymphocytes (61), indicating that T lymphocytes are important for virus clearance or TBE pathology (62,63).…”

Fatal Outcome of European Tick-borne Encephalitis after Vaccine Failure

“…Gelpi et al demonstrated that immunologic mechanisms contribute to nerve cell destruction in human TBE (14). In addition, CD4+ T cells play an important role in the TBEV vaccine response (15). An animal infection model with lymphocytic choriomeningitis virus demonstrated that a vaccine that elicits CD4+ T cells can result in lethal immunopathology following challenge with a persistently replicating virus (16).…”

Breadth and Dynamics of HLA-A2– and HLA-B7–Restricted CD8+ T Cell Responses against Nonstructural Viral Proteins in Acute Human Tick-Borne Encephalitis Virus Infection

“…All the major TBEV epitopes identified in the current study are located in nonstructural proteins of the virus, whereas T cell epitope studies in TBEV infection and vaccination so far have focused only on virion proteins (26,41). The majority of identified CD8 + T cell viral epitopes in YFV-17D or DENV are also derived from nonstructural proteins in these viruses (13,14,16,34).…”