HEV CD4 T cell immunity is defined by long-lasting capsid-specific responses which correlate with neutralizing antibodies

Zeitschrift für Gastroenterologie, vol. 60, pp. e475–e476

Abstract

Background and aims CD4 T cells play a crucial role in shaping the antiviral immune response. However, knowledge of their specificity and differentiation in the context of a Hepatitis E Virus (HEV) infection is limited. Thus, we aimed to longitudinally characterize the HEV-specific CD4 T cells and neutralizing antibodies that target either naked or quasi-enveloped viral particles in patients with acute and resolved Hepatitis E virus infection. Method In 7 acutely HEV infected and 33 resolved individuals, HEV-specific CD4 T cells targeting the 3 different open reading frames (ORF) were analysed by intracellular cytokine staining. Neutralizing antibodies to naked (nHEV) and quasi-enveloped (eHEV) virions were analysed in 72 patients. Newly generated HLA-DRB1*01:01 and*04:01 tetramers were used to examine surface markers and transcription factors on HEV-specific CD4 T cells. Results CD4 T cells demonstrated robust and multi-specific responses towards the viral capsid (ORF2) and non-structural polyprotein (NSP, ORF1). In contrast, weaker phosphoprotein (ORF3)-specific T cell responses were detected. Overall, in acutely infected individuals a stronger and broader T cell response were observed. Capsid-specific IFN-g- or IL-21-positive CD4 T cells associated strongly with total IgG- and neutralizing antibody titers against nHEV. Similarly, the lack of phosphoprotein-specific T cell responses was mirrored by only weak antibody responses against eHEV virions. Furthermore, after viral eradication, alterations from a highly activated Th1 and Tfh cell phenotype to a diverse memory population can be detected in capsid-specific CD4 T cells. Conclusion In summary, our findings provide insights into the immune landscape of CD4 T cells against HEV. The results indicate a strong preservation of capsid- and NSP-specific CD4 T cell responses, as well as the establishment of a robust HEV-specific memory compartment and suggest a less immunogenic phosphoprotein. Publication History Article published online: 19 August 2022 © 2022. Thieme. All rights reserved. Georg Thieme Verlag Rüdigerstraße 14, 70469 Stuttgart, Germany

Authors 11

1. Benedikt Csernalabics

   University Medical Center Freiburg

   Affiliation as printed

   Universitätsklinikum Freiburg, Klinik für Innere Medizin II, Freiburg im Breisgau, Deutschland

2. Katharina Zoldan

   University Medical Center Freiburg

   Affiliation as printed

   Universitätsklinikum Freiburg, Klinik für Innere Medizin II, Freiburg im Breisgau, Deutschland

3. Marcus Panning

   University of Freiburg · University Medical Center Freiburg

   Affiliation as printed

   Universitätsklinikum Freiburg, Institut für Virologie, Freiburg im Breisgau, Deutschland

4. Philipp Alexander Reuken

   Jena University Hospital

   Affiliation as printed

   Universitätsklinikum Jena, Klinik für Innere Medizin IV, Jena, Deutschland

5. Tony Bruns Aachen Klinik für Innere Medizin III

   Universitätsklinikum Aachen · RWTH Aachen University

   Affiliation as printed

   Universitätsklinikum RWTH Aachen, Klinik für Innere Medizin III, Aachen, Deutschland

6. Christoph Neumann‐Haefelin

   University Medical Center Freiburg

   Affiliation as printed

   Universitätsklinikum Freiburg, Klinik für Innere Medizin II, Freiburg im Breisgau, Deutschland

7. Bertram Bengsch

   University Medical Center Freiburg

   Affiliation as printed

   Universitätsklinikum Freiburg, Klinik für Innere Medizin II, Freiburg im Breisgau, Deutschland

8. Maike Hofmann

   University Medical Center Freiburg

   Affiliation as printed

   Universitätsklinikum Freiburg, Klinik für Innere Medizin II, Freiburg im Breisgau, Deutschland

9. Robert Thimme

   University Medical Center Freiburg

   Affiliation as printed

   Universitätsklinikum Freiburg, Klinik für Innere Medizin II, Freiburg im Breisgau, Deutschland

10. Viet Loan Dao Thi

    Heidelberg University · University Hospital Heidelberg

    Affiliation as printed

    Universitätsklinikum Heidelberg, Department of Infectious Diseases and Virology, Heidelberg, Deutschland

11. Tobias Boettler

    University Medical Center Freiburg

    Affiliation as printed

    Universitätsklinikum Freiburg, Klinik für Innere Medizin II, Freiburg im Breisgau, Deutschland