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Immunohorizons. 2018 Jul 2;2(6):172-184. doi: 10.4049/immunohorizons.1800029.

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.

Author information

1
Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, 141 86 Stockholm, Sweden.
2
Science for Life Laboratory, Department of Medicine, Solna, Karolinska Institutet, 10450 Stockholm, Sweden.
3
Division of Infectious Diseases, Karolinska University Hospital Solna, 171 76 Stockholm, Sweden.
4
Department of Infectious Diseases, Medical Academy, Lithuanian University of Health Sciences, 47116 Kaunas, Lithuania.
5
Section for Cellular Therapy, Department of Oncology, Oslo University Hospital, 0379 Oslo, Norway.
6
Department of Infectious Diseases, Karolinska University Hospital, 14186 Stockholm, Sweden; and.
7
Division of Molecular Oncology and Immunology, Netherlands Cancer Institute, 1066 CX Amsterdam, the Netherlands.
8
Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, 141 86 Stockholm, Sweden; sara.gredmark.russ@ki.se.

Abstract

Tick-borne encephalitis virus (TBEV) is a leading cause of viral meningoencephalitis in many parts of Europe and eastwards in Asia, with high morbidity and often long-term neurologic sequelae. With no treatment available, studies of the immune response to TBEV are essential for the understanding of the immunopathogenesis of tick-borne encephalitis and for the development of therapeutics. We have previously demonstrated that CD8+ T cell responses in peripheral blood in patients with acute TBEV peak at around 7 d after hospitalization in the neuroinvasive phase of the disease. In this study, we identified six novel TBEV HLA-A2- and HLA-B7-restricted epitopes, all derived from the nonstructural proteins of TBEV. This identification allowed for a comprehensive phenotypic and temporal analysis of the HLA-A2- and HLA-B7-restricted Ag-specific CD8+ T cell response during the acute stages of human TBEV infection. HLA-A2- and HLA-B7-restricted TBEV epitope-specific effector cells predominantly displayed a CD45RA-CCR7-CD27+CD57- phenotype at day 7, which transitioned into separate distinct phenotypes for HLA-A2- and HLA-B7-restricted TBEV-specific CD8+ T cells, respectively. At day 21, the most prevalent phenotype in the HLA-A2-restricted CD8+ T cell populations was CD45RA-CCR7-CD27+CD57+, whereas the HLA-B7-restricted CD8+ T cell population was predominantly CD45RA+CCR7-CD27+CD57+ Almost all TBEV epitope-specific CD8+ T cells expressed α4 and β1 integrins at days 7 and 21, whereas the bulk CD8+ T cells expressed lower integrin levels. Taken together, human TBEV infection elicits broad responses to multiple epitopes, predominantly derived from the nonstructural part of the virus, establishing distinct maturation patterns for HLA-A2- and HLA-B7-restricted TBEV epitope-specific CD8+ T cells.

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