Thymic CD4 T cell selection requires attenuation of March8-mediated MHCII turnover in cortical epithelial cells through CD83
Deficiency of CD83 in thymic epithelial cells (TECs) dramatically impairs thymic CD4 T cell selection. CD83 can exert cell-intrinsic and –extrinsic functions through discrete protein domains, but it remains unclear how CD83’s capacity to operate through these alternative functional modules relates t...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | en_US |
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Rockefeller University Press
2017
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| Online Access: | http://hdl.handle.net/1721.1/107138 https://orcid.org/0000-0002-1090-6071 |
| _version_ | 1826196718674247680 |
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| author | von Rohrscheidt, Julia Petrozziello, Elisabetta Nedjic, Jelena Federle, Christine Krzyzak, Lena Ishido, Satoshi Steinkasserer, Alexander Klein, Ludger Ploegh, Hidde |
| author2 | Massachusetts Institute of Technology. Department of Biology |
| author_facet | Massachusetts Institute of Technology. Department of Biology von Rohrscheidt, Julia Petrozziello, Elisabetta Nedjic, Jelena Federle, Christine Krzyzak, Lena Ishido, Satoshi Steinkasserer, Alexander Klein, Ludger Ploegh, Hidde |
| author_sort | von Rohrscheidt, Julia |
| collection | MIT |
| description | Deficiency of CD83 in thymic epithelial cells (TECs) dramatically impairs thymic CD4 T cell selection. CD83 can exert cell-intrinsic and –extrinsic functions through discrete protein domains, but it remains unclear how CD83’s capacity to operate through these alternative functional modules relates to its crucial role in TECs. In this study, using viral reconstitution of gene function in TECs, we found that CD83’s transmembrane domain is necessary and sufficient for thymic CD4 T cell selection. Moreover, a ubiquitination-resistant MHCII variant restored CD4 T cell selection in Cd83[superscript −/−] mice. Although during dendritic cell maturation CD83 is known to stabilize MHCII through opposing the ubiquitin ligase March1, regulation of March1 did not account for CD83’s TEC-intrinsic role. Instead, we provide evidence that MHCII in cortical TECs (cTECs) is targeted by March8, an E3 ligase of as yet unknown physiological substrate specificity. Ablating March8 in Cd83[superscript −/−] mice restored CD4 T cell development. Our results identify CD83-mediated MHCII stabilization through antagonism of March8 as a novel functional adaptation of cTECs for T cell selection. Furthermore, these findings suggest an intriguing division of labor between March1 and March8 in controlling inducible versus constitutive MHCII expression in hematopoietic antigen-presenting cells versus TECs. |
| first_indexed | 2024-09-23T10:36:43Z |
| format | Article |
| id | mit-1721.1/107138 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T10:36:43Z |
| publishDate | 2017 |
| publisher | Rockefeller University Press |
| record_format | dspace |
| spelling | mit-1721.1/1071382022-09-30T21:47:31Z Thymic CD4 T cell selection requires attenuation of March8-mediated MHCII turnover in cortical epithelial cells through CD83 von Rohrscheidt, Julia Petrozziello, Elisabetta Nedjic, Jelena Federle, Christine Krzyzak, Lena Ishido, Satoshi Steinkasserer, Alexander Klein, Ludger Ploegh, Hidde Massachusetts Institute of Technology. Department of Biology Whitehead Institute for Biomedical Research Ploegh, Hidde Deficiency of CD83 in thymic epithelial cells (TECs) dramatically impairs thymic CD4 T cell selection. CD83 can exert cell-intrinsic and –extrinsic functions through discrete protein domains, but it remains unclear how CD83’s capacity to operate through these alternative functional modules relates to its crucial role in TECs. In this study, using viral reconstitution of gene function in TECs, we found that CD83’s transmembrane domain is necessary and sufficient for thymic CD4 T cell selection. Moreover, a ubiquitination-resistant MHCII variant restored CD4 T cell selection in Cd83[superscript −/−] mice. Although during dendritic cell maturation CD83 is known to stabilize MHCII through opposing the ubiquitin ligase March1, regulation of March1 did not account for CD83’s TEC-intrinsic role. Instead, we provide evidence that MHCII in cortical TECs (cTECs) is targeted by March8, an E3 ligase of as yet unknown physiological substrate specificity. Ablating March8 in Cd83[superscript −/−] mice restored CD4 T cell development. Our results identify CD83-mediated MHCII stabilization through antagonism of March8 as a novel functional adaptation of cTECs for T cell selection. Furthermore, these findings suggest an intriguing division of labor between March1 and March8 in controlling inducible versus constitutive MHCII expression in hematopoietic antigen-presenting cells versus TECs. 2017-02-23T20:17:54Z 2017-02-23T20:17:54Z 2016-08 2016-02 Article http://purl.org/eprint/type/JournalArticle 0022-1007 1540-9538 http://hdl.handle.net/1721.1/107138 von Rohrscheidt, Julia et al. “Thymic CD4 T Cell Selection Requires Attenuation of March8-Mediated MHCII Turnover in Cortical Epithelial Cells through CD83.” The Journal of Experimental Medicine 213.9 (2016): 1685–1694. https://orcid.org/0000-0002-1090-6071 en_US http://dx.doi.org/10.1084/jem.20160316 The Journal of Experimental Medicine Creative Commons Attribution-Noncommercial-Share Alike http://creativecommons.org/licenses/by-nc-sa/3.0/ application/pdf Rockefeller University Press Rockefeller University Press |
| spellingShingle | von Rohrscheidt, Julia Petrozziello, Elisabetta Nedjic, Jelena Federle, Christine Krzyzak, Lena Ishido, Satoshi Steinkasserer, Alexander Klein, Ludger Ploegh, Hidde Thymic CD4 T cell selection requires attenuation of March8-mediated MHCII turnover in cortical epithelial cells through CD83 |
| title | Thymic CD4 T cell selection requires attenuation of March8-mediated MHCII turnover in cortical epithelial cells through CD83 |
| title_full | Thymic CD4 T cell selection requires attenuation of March8-mediated MHCII turnover in cortical epithelial cells through CD83 |
| title_fullStr | Thymic CD4 T cell selection requires attenuation of March8-mediated MHCII turnover in cortical epithelial cells through CD83 |
| title_full_unstemmed | Thymic CD4 T cell selection requires attenuation of March8-mediated MHCII turnover in cortical epithelial cells through CD83 |
| title_short | Thymic CD4 T cell selection requires attenuation of March8-mediated MHCII turnover in cortical epithelial cells through CD83 |
| title_sort | thymic cd4 t cell selection requires attenuation of march8 mediated mhcii turnover in cortical epithelial cells through cd83 |
| url | http://hdl.handle.net/1721.1/107138 https://orcid.org/0000-0002-1090-6071 |
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