Flavivirus-induced up-regulation of MHC class I antigens; implications for the induction of CD8+ T-cell-mediated autoimmunity.
Infection of a wide variety of cells of human, mouse and other species' origin by flaviviruses such as WNV, YF, Den, MVE, KUN and JE, increases the cell-surface expression of MHC class I. This MHC class I up-regulation is not due to increased MHC class I synthesis per se, but the result of increased peptide availability in the ER for MHC class I assembly. This is most likely due to the interaction of the viral polyprotein with the ER membrane during viral replication. Flavivirus infection can overcome peptide deficiency in TAP-deficient or non-permissive cell lines such as RMA-S and Syrian hamster cells, BHK and NIL-2. The consequence of this increased MHC class I expression manifests itself in reduced susceptibility to NK cells and augmented lysis by Tc cells. In mice, long-term flavivirus-immune Tc cell memory formation is impaired, following the appearance of strong anti-self Tc cell reactivity observed in in vitro cultures from splenocytes of flavivirus-primed animals. We hypothesize that flavivirus-induced MHC class I up-regulation leads to transient T-cell autoimmunity, followed by down-regulation of both autoimmunity and virus-specific Tc cell memory. Furthermore, we speculate that flavivirus infections of humans in the tropics may be responsible for the observed lower incidence of overt autoimmunity in these geographic regions than in temperate climates where flaviviruses are not endemic.
Lobigs
M
M
Division of Immunology and Cell Biology, John Curtin School of Medical Research, Australian National University, Canberra, Australia.
Blanden
R V
RV
Müllbacher
A
A
D000818:Animals; D015551:Autoimmunity / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D005416:Flavivirus / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D006801:Humans; D015854:Up-Regulation / Q000276:immunology*
D015395:Histocompatibility Antigens Class I