Journal
JOURNAL OF EXPERIMENTAL MEDICINE
Volume 213, Issue 9, Pages 1695-1703Publisher
ROCKEFELLER UNIV PRESS
DOI: 10.1084/jem.20160312
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Funding
- National Health and Medical Research Council (NHMRC) of Australia program [1016629, 1071916]
- NHMRC project [1078763, 1049724, 1058193]
- Human Frontier Science Program [RGP0064]
- Australian Research Council Discovery Project [DP110101383]
- University of Melbourne International Research scholarships
- National Health and Medical Research Council of Australia [1058193, 1078763] Funding Source: NHMRC
- Grants-in-Aid for Scientific Research [24112003] Funding Source: KAKEN
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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 (Cd83(anu/anu) mice) have impaired CD4(+) T cell selection, but deleting March8 in Cd83(anu/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.
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