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Chapter 9: Immunology of TBEV infection

Role of T cells in TBE pathogenesis led peptide-MHC complexes. 66,67 Antigen-
specific T cells recognize the peptides present-
Even though T cells participate in the immune
ed on these complexes and bind to them. This
response to TBEV, the role of these cells in the binding can then be detected using flow
outcome of TBE is not clear. One study cytometry. This is an invaluable tool to study
suggests that T cell infiltration into the CNS
virus-specific cells in patients including TBEV-
during TBEV infection might contribute to a infection.
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favourable disease outcome. In vivo studies
of CCR5-deficient mice infected with Langat In total, seven TBEV-specific peptides have
virus, show a delayed influx of CD4 and CD8 T been identified, and all of them are located in
cells into the CNS, increased viral replication nonstructural (NS) proteins of the virus. 60,61
and decreased survival of these mice, The majority of previously identified CD8 T cell
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suggesting a protective role of T cells. Other viral peptides in other flaviviral infections,
conflicting studies suggest immunopatho- such as YFV and DENV, are also derived from
logical rather than protective role of CD8 T NS proteins. 68-70
cells in TBE. Brain tissue biopsies from fatal Immunodominant regions of viral proteins can
TBE cases show cytotoxic T cell infiltration in be determined by stimulating cells with
4
close proximity of TBEV-infected neurons. In
peptides based on the full viral protein
addition, CD8 deficient mice have a prolonged
sequences. Antigen specific cells upon binding
survival as compared to immunocompetent to such peptides might initiate cytokine
mice during TBEV infection, and this effect is release (like IL-2) which can be measured for
independent of viral load in the periphery or each peptide. Such studies on CD4 T cells after
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the brain. This immunopathology is primarily
TBEV infection and vaccination identified
mediated by CD8 T cells and not CD4 T cells, as immunodominant regions of structural viral
shown by shorter time of survival of proteins. 71,72 Both vaccinated and infected
immunodeficient SCID mice receiving CD8 T individuals responded to similar regions of
cells, whereas adoptive transfer of CD4 T cells TBEV structural proteins, even if the response
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increases the survival time. Yet, other mouse
was higher in the vaccinated cohort. Another
studies that compared mice challenged with study showed that, full recombinant structural
TBEV that died or recovered, did not detect TBEV proteins trigger CD4 T cells, but not CD8
any differences in T cells numbers in the brains 73
T cells in TBE-vaccinated individuals. There-
of the two groups, even if the cell numbers
fore, CD4 T cell responses seem to be skewed
were increased in both groups as compared to toward recognition of structural proteins,
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uninfected mice. Interestingly, T cell whereas CD8 T cell responses are skewed
receptor antigen specificity might determine toward recognition of NS proteins.
the severity of TBEV-infection in mice, as T cell
clones that express certain TCRs accumulate in
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the brains of mice dying from TBEV. These
conflicting studies highlight the need for Inflammation during TBE
further research to understand the role of T
Inflammation upon acute infections is an
cells in the context of TBE pathogenesis.
important part of the immune response
essential for the elimination of pathogens. On
T cell antigen specificity in TBEV infection and the other hand, excessive inflammation may
vaccination be harmful to the host. Many cells contribute
to the inflammatory processes during
Antigen-specific T cells can be detected by infections to produce different cytokines,
artificially generated and fluorescently label-
chemokines and growth factors. During TBEV

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