Specificity and Dynamics of Effector and Memory CD8 T Cell Responses in Human Tick-Borne Encephalitis Virus Infection

Abstract

Tick-borne encephalitis virus (TBEV) is transferred to humans by ticks. The virus causes tick-borne encephalitis (TBE) with symptoms such as meningitis and meningoencephalitis. About one third of the patients suffer from long-lasting sequelae after clearance of the infection. Studies of the immune response during TBEV-infection are essential to the understanding of host responses to TBEV-infection and for the development of therapeutics. Here, we studied in detail the primary CD8 T cell response to TBEV in patients with acute TBE. Peripheral blood CD8 T cells mounted a considerable response to TBEV-infection as assessed by Ki67 and CD38 co-expression. These activated cells showed a CD45RA-CCR7-CD127- phenotype at day 7 after hospitalization, phenotypically defining them as effector cells. An immunodominant HLA-A2-restricted TBEV epitope was identified and utilized to study the characteristics and temporal dynamics of the antigen-specific response. The functional profile of TBEV-specific CD8 T cells was dominated by variants of mono-functional cells as the effector response matured. Antigen-specific CD8 T cells predominantly displayed a distinct Eomes+Ki67+T-bet+ effector phenotype at the peak of the response, which transitioned to an Eomes-Ki67-T-bet+ phenotype as the infection resolved and memory was established. These transcription factors thus characterize and discriminate stages of the antigen-specific T cell response during acute TBEV-infection. Altogether, CD8 T cells responded strongly to acute TBEV infection and passed through an effector phase, prior to gradual differentiation into memory cells with distinct transcription factor expression-patterns throughout the different phases.

Tick-Borne Flaviviruses, with a Focus on Powassan Virus

“…DCs are also responsible for generating protective CD8 ϩ T-cell immunity using molecular signaling (104). The CD8 ϩ T-cell response was recently examined in depth in acute human TBEV infections, including temporal dynamics, specificity, and functional and phenotypical characteristics of the response (105). Another recent study suggested some major differences in the natural killer (NK) T-cell response against human TBEV infection compared to other human viral infections (106).…”

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

“…1A, Supplemental Fig. 2A) (16). Significant CD8 + T cell responses were also observed against the HLA-B7-restricted epitopes B7-3 (RPVWKDARM), B7-4 (RVRFHSPAV), and B7-6 (LPLGHRLWL) (major epitopes) ( Fig.…”

“…Monitoring of Ag-specific CD8 + T cell populations is essential to dissect distinct characteristics in immune responses to a certain pathogen and to delineate the role of virus-specific CD8 + T cells during acute and persistent infections as well as long-term protection. We have previously demonstrated that CD8 + T cell responses in peripheral blood of TBE patients peak at around 7 d after hospitalization during the acute neuroinvasive phase of the disease (16). In that study, we identified one HLA-A2-restricted TBEV epitope and demonstrated that TBEV-specific CD8 + T cells display a distinctive phenotypic and functional profile, paired with a distinct transcription factor expression pattern during the peak of activation.…”

“…Peripheral blood was obtained from 10 confirmed TBEV-infected patients from the Department of Infectious Disease at the Lithuanian University of Health Sciences in Kaunas, Lithuania. The donors in this study consisted of a separate cohort from previously published work (16,17). TBEV infection was confirmed by specific IgM-and/or IgG-TBEV analysis in serum according to standard clinical diagnostic criteria together with symptoms associated with meningitis or meningoencephalitis.…”

“…In that study, we identified one HLA-A2-restricted TBEV epitope and demonstrated that TBEV-specific CD8 + T cells display a distinctive phenotypic and functional profile, paired with a distinct transcription factor expression pattern during the peak of activation. However, the fact that only one TBEV CD8 + T cell epitope had been characterized (16) clearly limited the possibilities to fully characterize the temporal aspects of the response and the contribution of different HLA class I-types to TBEV-specific CD8 + T cell responses in humans. Furthermore, these previous investigations did not encompass any studies on properties bearing characteristics of a migratory capacity to the CNS.…”