Abstract
Major histocompatibility complex class II (MHC II) expression is tightly regulated, being subjected to cell type-specific mechanisms that closely control its levels at the cell surface. Ubiquitination by the E3 ubiquitin ligase MAR CH 1 regulates MHC II expression in dendritic cells and B cells. In this study, we demonstrate that the related ligase MAR CH 8 is responsible for regulating surface MHC II in thymic epithelial cells (TECs). March8-/- mice have elevated MHC II at the surface of cortical TECs and autoimmune regulator (AIRE)- medullary TECs (mTECs), but not AIRE+ mTECs. Despite this, thymic and splenic CD4+ T cell numbers and repertoires remained unaltered in March8-/- mice. Notably, the ubiquitination of MHC II by MAR CH 8 is controlled by CD83. Mice expressing a mutated form of CD83 (Cd83anu/anu mice) have impaired CD4+ T cell selection, but deleting March8 in Cd83anu/anu mice restored CD4+ T cell selection to normal levels. Therefore, orchestrated regulation of MHC II surface expression in TECs by MAR CH 8 and CD83 plays a major role in CD4+ T cell selection. Our results also highlight the specialized use of ubiquitinating machinery in distinct antigen-presenting cell types, with important functional consequences and implications for therapeutic manipulation.
| Original language | English |
|---|---|
| Pages (from-to) | 1695-1703 |
| Number of pages | 9 |
| Journal | Journal of Experimental Medicine |
| Volume | 213 |
| Issue number | 9 |
| DOIs | |
| Publication status | Published - 8 Aug 2016 |
Cite this
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Ubiquitin ligase MARCH 8 cooperates with CD83 to control surface MHC II expression in thymic epithelium and CD4 T cell selection. / Liu, Haiyin; Jain, Reema; Guan, Jing; Vuong, Vivian; Ishido, Satoshi; La Gruta, Nicole L.; Gray, Daniel H.; Villadangos, Jose A.; Mintern, Justine D.
In: Journal of Experimental Medicine, Vol. 213, No. 9, 08.08.2016, p. 1695-1703.Research output: Contribution to journal › Article › Research › peer-review
TY - JOUR
T1 - Ubiquitin ligase MARCH 8 cooperates with CD83 to control surface MHC II expression in thymic epithelium and CD4 T cell selection
AU - Liu, Haiyin
AU - Jain, Reema
AU - Guan, Jing
AU - Vuong, Vivian
AU - Ishido, Satoshi
AU - La Gruta, Nicole L.
AU - Gray, Daniel H.
AU - Villadangos, Jose A.
AU - Mintern, Justine D.
PY - 2016/8/8
Y1 - 2016/8/8
N2 - Major histocompatibility complex class II (MHC II) expression is tightly regulated, being subjected to cell type-specific mechanisms that closely control its levels at the cell surface. Ubiquitination by the E3 ubiquitin ligase MAR CH 1 regulates MHC II expression in dendritic cells and B cells. In this study, we demonstrate that the related ligase MAR CH 8 is responsible for regulating surface MHC II in thymic epithelial cells (TECs). March8-/- mice have elevated MHC II at the surface of cortical TECs and autoimmune regulator (AIRE)- medullary TECs (mTECs), but not AIRE+ mTECs. Despite this, thymic and splenic CD4+ T cell numbers and repertoires remained unaltered in March8-/- mice. Notably, the ubiquitination of MHC II by MAR CH 8 is controlled by CD83. Mice expressing a mutated form of CD83 (Cd83anu/anu mice) have impaired CD4+ T cell selection, but deleting March8 in Cd83anu/anu mice restored CD4+ T cell selection to normal levels. Therefore, orchestrated regulation of MHC II surface expression in TECs by MAR CH 8 and CD83 plays a major role in CD4+ T cell selection. Our results also highlight the specialized use of ubiquitinating machinery in distinct antigen-presenting cell types, with important functional consequences and implications for therapeutic manipulation.
AB - Major histocompatibility complex class II (MHC II) expression is tightly regulated, being subjected to cell type-specific mechanisms that closely control its levels at the cell surface. Ubiquitination by the E3 ubiquitin ligase MAR CH 1 regulates MHC II expression in dendritic cells and B cells. In this study, we demonstrate that the related ligase MAR CH 8 is responsible for regulating surface MHC II in thymic epithelial cells (TECs). March8-/- mice have elevated MHC II at the surface of cortical TECs and autoimmune regulator (AIRE)- medullary TECs (mTECs), but not AIRE+ mTECs. Despite this, thymic and splenic CD4+ T cell numbers and repertoires remained unaltered in March8-/- mice. Notably, the ubiquitination of MHC II by MAR CH 8 is controlled by CD83. Mice expressing a mutated form of CD83 (Cd83anu/anu mice) have impaired CD4+ T cell selection, but deleting March8 in Cd83anu/anu mice restored CD4+ T cell selection to normal levels. Therefore, orchestrated regulation of MHC II surface expression in TECs by MAR CH 8 and CD83 plays a major role in CD4+ T cell selection. Our results also highlight the specialized use of ubiquitinating machinery in distinct antigen-presenting cell types, with important functional consequences and implications for therapeutic manipulation.
UR - http://www.scopus.com/inward/record.url?scp=84984802042&partnerID=8YFLogxK
U2 - 10.1084/jem.20160312
DO - 10.1084/jem.20160312
M3 - Article
VL - 213
SP - 1695
EP - 1703
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
SN - 0022-1007
IS - 9
ER -