HSV-2 specifically down regulates HLA-C expression to render HSV-2-infected DCs susceptible to NK cell killing.
Both NK cells and CTLs kill virus-infected and tumor cells. However, the ways by which these killer cells recognize the infected or the tumorigenic cells are different, in fact almost opposite. CTLs are activated through the interaction of the TCR with MHC class I proteins. In contrast, NK cells are...
Saved in:
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2013-03-01
|
| Series: | PLoS Pathogens |
| Online Access: | https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1003226&type=printable |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849470808179605504 |
|---|---|
| author | Moran Elboim Inna Grodzovski Esther Djian Dana G Wolf Ofer Mandelboim |
| author_facet | Moran Elboim Inna Grodzovski Esther Djian Dana G Wolf Ofer Mandelboim |
| author_sort | Moran Elboim |
| collection | DOAJ |
| description | Both NK cells and CTLs kill virus-infected and tumor cells. However, the ways by which these killer cells recognize the infected or the tumorigenic cells are different, in fact almost opposite. CTLs are activated through the interaction of the TCR with MHC class I proteins. In contrast, NK cells are inhibited by MHC class I molecules. The inhibitory NK receptors recognize mainly MHC class I proteins and in this regard practically all of the HLA-C proteins are recognized by inhibitory NK cell receptors, while only certain HLA-A and HLA-B proteins interact with these receptors. Sophisticated viruses developed mechanisms to avoid the attack of both NK cells and CTLs through, for example, down regulation of HLA-A and HLA-B molecules to avoid CTL recognition, leaving HLA-C proteins on the cell surface to inhibit NK cell response. Here we provide the first example of a virus that through specific down regulation of HLA-C, harness the NK cells for its own benefit. We initially demonstrated that none of the tested HSV-2 derived microRNAs affect NK cell activity. Then we show that surprisingly upon HSV-2 infection, HLA-C proteins are specifically down regulated, rendering the infected cells susceptible to NK cell attack. We identified a motif in the tail of HLA-C that is responsible for the HSV-2-meduiated HLA-C down regulation and we show that the HLA-C down regulation is mediated by the viral protein ICP47. Finally we show that HLA-C proteins are down regulated from the surface of HSV-2 infected dendritic cells (DCs) and that this leads to the killing of DC by NK cells. Thus, we propose that HSV-2 had developed this unique and surprising NK cell-mediated killing strategy of infected DC to prevent the activation of the adaptive immunity. |
| format | Article |
| id | doaj-art-daa89b24f18f400d9411fba12a07aa75 |
| institution | Kabale University |
| issn | 1553-7366 1553-7374 |
| language | English |
| publishDate | 2013-03-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS Pathogens |
| spelling | doaj-art-daa89b24f18f400d9411fba12a07aa752025-08-20T03:25:03ZengPublic Library of Science (PLoS)PLoS Pathogens1553-73661553-73742013-03-0193e100322610.1371/journal.ppat.1003226HSV-2 specifically down regulates HLA-C expression to render HSV-2-infected DCs susceptible to NK cell killing.Moran ElboimInna GrodzovskiEsther DjianDana G WolfOfer MandelboimBoth NK cells and CTLs kill virus-infected and tumor cells. However, the ways by which these killer cells recognize the infected or the tumorigenic cells are different, in fact almost opposite. CTLs are activated through the interaction of the TCR with MHC class I proteins. In contrast, NK cells are inhibited by MHC class I molecules. The inhibitory NK receptors recognize mainly MHC class I proteins and in this regard practically all of the HLA-C proteins are recognized by inhibitory NK cell receptors, while only certain HLA-A and HLA-B proteins interact with these receptors. Sophisticated viruses developed mechanisms to avoid the attack of both NK cells and CTLs through, for example, down regulation of HLA-A and HLA-B molecules to avoid CTL recognition, leaving HLA-C proteins on the cell surface to inhibit NK cell response. Here we provide the first example of a virus that through specific down regulation of HLA-C, harness the NK cells for its own benefit. We initially demonstrated that none of the tested HSV-2 derived microRNAs affect NK cell activity. Then we show that surprisingly upon HSV-2 infection, HLA-C proteins are specifically down regulated, rendering the infected cells susceptible to NK cell attack. We identified a motif in the tail of HLA-C that is responsible for the HSV-2-meduiated HLA-C down regulation and we show that the HLA-C down regulation is mediated by the viral protein ICP47. Finally we show that HLA-C proteins are down regulated from the surface of HSV-2 infected dendritic cells (DCs) and that this leads to the killing of DC by NK cells. Thus, we propose that HSV-2 had developed this unique and surprising NK cell-mediated killing strategy of infected DC to prevent the activation of the adaptive immunity.https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1003226&type=printable |
| spellingShingle | Moran Elboim Inna Grodzovski Esther Djian Dana G Wolf Ofer Mandelboim HSV-2 specifically down regulates HLA-C expression to render HSV-2-infected DCs susceptible to NK cell killing. PLoS Pathogens |
| title | HSV-2 specifically down regulates HLA-C expression to render HSV-2-infected DCs susceptible to NK cell killing. |
| title_full | HSV-2 specifically down regulates HLA-C expression to render HSV-2-infected DCs susceptible to NK cell killing. |
| title_fullStr | HSV-2 specifically down regulates HLA-C expression to render HSV-2-infected DCs susceptible to NK cell killing. |
| title_full_unstemmed | HSV-2 specifically down regulates HLA-C expression to render HSV-2-infected DCs susceptible to NK cell killing. |
| title_short | HSV-2 specifically down regulates HLA-C expression to render HSV-2-infected DCs susceptible to NK cell killing. |
| title_sort | hsv 2 specifically down regulates hla c expression to render hsv 2 infected dcs susceptible to nk cell killing |
| url | https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1003226&type=printable |
| work_keys_str_mv | AT moranelboim hsv2specificallydownregulateshlacexpressiontorenderhsv2infecteddcssusceptibletonkcellkilling AT innagrodzovski hsv2specificallydownregulateshlacexpressiontorenderhsv2infecteddcssusceptibletonkcellkilling AT estherdjian hsv2specificallydownregulateshlacexpressiontorenderhsv2infecteddcssusceptibletonkcellkilling AT danagwolf hsv2specificallydownregulateshlacexpressiontorenderhsv2infecteddcssusceptibletonkcellkilling AT ofermandelboim hsv2specificallydownregulateshlacexpressiontorenderhsv2infecteddcssusceptibletonkcellkilling |