Page 101 - TBE_Book_V2_2019

Chapter 4: Pathogenesis of TBE

only by neutralization; therefore, because Studies in humans showed that CD8 T cells
limited virus replication does occur, this responded strongly to acute TBEV infection
indicates that mechanisms of protection from and passed through an effector phase, prior to
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disease exist other than sterilizing immunity. gradual differentiation into memory cells,
indicating that TBEV infection induces a robust
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Cellular Immunity CD8 T cell response. Comparable studies in
mice revealed that the number and activation
In addition to effective humoral immunity, the of T cells in the CNS have no impact in the
activation of cellular immunity is usually outcome of infection; both dying and recover-
required for clearance of established infection. ing mice showed no difference in number and
Distinct T cell subsets play a key role in the activation status of T cells upon TBEV
induction of protective immune response infection. However, differences were seen in
against TBEV infections. CD4+ T cells are the specific T cell clones accumulating in the
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essential in priming the TBEV-specific antibody brain.
response and sustaining the CD8+ T cell
response. However, results from studies in Besides their role in antiviral response, CD8+ T
mice lacking B cells or CD4+ T cells during cells are also believed to contribute to CNS
TBEV infections are missing. Nonetheless, pathogenesis. In brain autopsy samples from
mice lacking type I IFN signaling develop a TBEV-diagnosed individuals, inverse topo-
normal antibody response during LGTV graphical correlation of inflammation and
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infection but are not protected from severe TBEV-infected areas has been reported.
infection. 5,20 Inflammatory infiltrates are predominantly
composed of T cells and macrophages/
Cytotoxic T lymphocytes (CTL) recognize viral microglia. In regions with less infiltration CTL
peptides presented on major histo- are closely associated with TBEV-infected
compatibility complex (MHC) class I molecules neurons. These findings suggest that
and eliminate cells producing abnormal or immunologic mechanisms can contribute to
foreign proteins, specifically virus infected nerve cell destruction in human disease. In
cells. CD8+ CTLs control viral replication via immune deficient SCID mice or mice lacking
distinct mechanisms: noncytolytically by CD8 T cells an increased survival upon TBEV
secretion of IFN-γ or TNFα or cytolytically by infection was shown. Adaptive transfer of
cytotoxic proteins like granzyme B and CD8+ T cells in SCID mice decreases median
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perforin. Long-term immune surveillance survival time. Although these data suggest a
effector cells react more quickly against the contribution of CD8 T cells in pathogenesis,
same virus after a primary infection. surprisingly, this effect is independent of viral
replication in the periphery and the CNS. The
The effects of TBEV infection on T cells are less
pathogenicity of virus strains also seems to
studied. Ex vivo infection of human blood cells
influence the effect of CD8 T cells on the
leads to an activated phenotype of T cells with outcome of infection. Whereas CD8+ T-cell-
low-pathogenic TBEV, whereas the highly deficient SCID mice succumb later from
pathogenic TBEV suppresses T-cell activa- infection with high pathogenic TBEV strains, a
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tion. It is unclear whether T cells are directly
survival advantage was shown upon infection
infected by TBEV, but no infection of T cells 19
with low pathogenic strains.
was detectable in highly susceptible IFNAR
5
mice infected by Langat virus, which makes Although viral infection with LGTV leads to an
direct infection of T cells unlikely. accumulation of CD4+ and CD8+ T cells in the
CNS, no increased numbers of apoptotic cells
5,20
were detectable.
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