A genetic screen in macrophages identifies new regulators of IFNγ-inducible MHCII that contribute to T cell activation
Cytokine-mediated activation of host immunity is central to the control of pathogens. Interferon-gamma (IFNγ) is a key cytokine in protective immunity that induces major histocompatibility complex class II molecules (MHCII) to amplify CD4+ T cell activation and effector function. Despite its central...
| Main Authors: | , , , , , , , , |
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| Format: | Article |
| Language: | English |
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eLife Sciences Publications Ltd
2021-11-01
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| Series: | eLife |
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| Online Access: | https://elifesciences.org/articles/65110 |
| _version_ | 1811227712840269824 |
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| author | Michael C Kiritsy Laurisa M Ankley Justin Trombley Gabrielle P Huizinga Audrey E Lord Pontus Orning Roland Elling Katherine A Fitzgerald Andrew J Olive |
| author_facet | Michael C Kiritsy Laurisa M Ankley Justin Trombley Gabrielle P Huizinga Audrey E Lord Pontus Orning Roland Elling Katherine A Fitzgerald Andrew J Olive |
| author_sort | Michael C Kiritsy |
| collection | DOAJ |
| description | Cytokine-mediated activation of host immunity is central to the control of pathogens. Interferon-gamma (IFNγ) is a key cytokine in protective immunity that induces major histocompatibility complex class II molecules (MHCII) to amplify CD4+ T cell activation and effector function. Despite its central role, the dynamic regulation of IFNγ-induced MHCII is not well understood. Using a genome-wide CRISPR-Cas9 screen in murine macrophages, we identified genes that control MHCII surface expression. Mechanistic studies uncovered two parallel pathways of IFNγ-mediated MHCII control that require the multifunctional glycogen synthase kinase three beta (GSK3β) or the mediator complex subunit 16 (MED16). Both pathways control distinct aspects of the IFNγ response and are necessary for IFNγ-mediated induction of the MHCII transactivator Ciita, MHCII expression, and CD4+ T cell activation. Our results define previously unappreciated regulation of MHCII expression that is required to control CD4+ T cell responses. |
| first_indexed | 2024-04-12T09:46:20Z |
| format | Article |
| id | doaj.art-27cb52ae4b22483f922ca3e06412e9cd |
| institution | Directory Open Access Journal |
| issn | 2050-084X |
| language | English |
| last_indexed | 2024-04-12T09:46:20Z |
| publishDate | 2021-11-01 |
| publisher | eLife Sciences Publications Ltd |
| record_format | Article |
| series | eLife |
| spelling | doaj.art-27cb52ae4b22483f922ca3e06412e9cd2022-12-22T03:37:56ZengeLife Sciences Publications LtdeLife2050-084X2021-11-011010.7554/eLife.65110A genetic screen in macrophages identifies new regulators of IFNγ-inducible MHCII that contribute to T cell activationMichael C Kiritsy0https://orcid.org/0000-0001-8364-8088Laurisa M Ankley1Justin Trombley2Gabrielle P Huizinga3Audrey E Lord4Pontus Orning5https://orcid.org/0000-0002-6177-6916Roland Elling6Katherine A Fitzgerald7Andrew J Olive8https://orcid.org/0000-0003-3441-3113Department of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, United StatesDepartment of Microbiology & Molecular Genetics, College of Osteopathic Medicine, Michigan State University, East Lansing, United StatesDepartment of Microbiology & Molecular Genetics, College of Osteopathic Medicine, Michigan State University, East Lansing, United StatesDepartment of Microbiology & Molecular Genetics, College of Osteopathic Medicine, Michigan State University, East Lansing, United StatesDepartment of Microbiology and Physiological Systems, University of Massachusetts Medical School, Worcester, United StatesDivision of Infectious Disease and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, United StatesDivision of Infectious Disease and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, United StatesDivision of Infectious Disease and Immunology, Department of Medicine, University of Massachusetts Medical School, Worcester, United StatesDepartment of Microbiology & Molecular Genetics, College of Osteopathic Medicine, Michigan State University, East Lansing, United StatesCytokine-mediated activation of host immunity is central to the control of pathogens. Interferon-gamma (IFNγ) is a key cytokine in protective immunity that induces major histocompatibility complex class II molecules (MHCII) to amplify CD4+ T cell activation and effector function. Despite its central role, the dynamic regulation of IFNγ-induced MHCII is not well understood. Using a genome-wide CRISPR-Cas9 screen in murine macrophages, we identified genes that control MHCII surface expression. Mechanistic studies uncovered two parallel pathways of IFNγ-mediated MHCII control that require the multifunctional glycogen synthase kinase three beta (GSK3β) or the mediator complex subunit 16 (MED16). Both pathways control distinct aspects of the IFNγ response and are necessary for IFNγ-mediated induction of the MHCII transactivator Ciita, MHCII expression, and CD4+ T cell activation. Our results define previously unappreciated regulation of MHCII expression that is required to control CD4+ T cell responses.https://elifesciences.org/articles/65110IFN-gammaMHCII expressionCD4+ T cell activationmacrophages |
| spellingShingle | Michael C Kiritsy Laurisa M Ankley Justin Trombley Gabrielle P Huizinga Audrey E Lord Pontus Orning Roland Elling Katherine A Fitzgerald Andrew J Olive A genetic screen in macrophages identifies new regulators of IFNγ-inducible MHCII that contribute to T cell activation eLife IFN-gamma MHCII expression CD4+ T cell activation macrophages |
| title | A genetic screen in macrophages identifies new regulators of IFNγ-inducible MHCII that contribute to T cell activation |
| title_full | A genetic screen in macrophages identifies new regulators of IFNγ-inducible MHCII that contribute to T cell activation |
| title_fullStr | A genetic screen in macrophages identifies new regulators of IFNγ-inducible MHCII that contribute to T cell activation |
| title_full_unstemmed | A genetic screen in macrophages identifies new regulators of IFNγ-inducible MHCII that contribute to T cell activation |
| title_short | A genetic screen in macrophages identifies new regulators of IFNγ-inducible MHCII that contribute to T cell activation |
| title_sort | genetic screen in macrophages identifies new regulators of ifnγ inducible mhcii that contribute to t cell activation |
| topic | IFN-gamma MHCII expression CD4+ T cell activation macrophages |
| url | https://elifesciences.org/articles/65110 |
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