IFNγ induces epigenetic programming of human T-bet hi B cells and promotes TLR7/8 and IL-21 induced differentiation
Although B cells expressing the IFNγR or the IFNγ-inducible transcription factor T-bet promote autoimmunity in Systemic Lupus Erythematosus (SLE)-prone mouse models, the role for IFNγ signaling in human antibody responses is unknown. We show that elevated levels of IFNγ in SLE patients correlate wit...
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| Veröffentlicht in: | eLife 2019-05, Vol.8 |
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| creator | Zumaquero, Esther Stone, Sara L Scharer, Christopher D Jenks, Scott A Nellore, Anoma Mousseau, Betty Rosal-Vela, Antonio Botta, Davide Bradley, John E Wojciechowski, Wojciech Ptacek, Travis Danila, Maria I Edberg, Jeffrey C Bridges, Jr, S Louis Kimberly, Robert P Chatham, W Winn Schoeb, Trenton R Rosenberg, Alexander F Boss, Jeremy M Sanz, Ignacio Lund, Frances E |
| description | Although B cells expressing the IFNγR or the IFNγ-inducible transcription factor T-bet promote autoimmunity in Systemic Lupus Erythematosus (SLE)-prone mouse models, the role for IFNγ signaling in human antibody responses is unknown. We show that elevated levels of IFNγ in SLE patients correlate with expansion of the T-bet expressing IgD
CD27
CD11c
CXCR5
(DN2) pre-antibody secreting cell (pre-ASC) subset. We demonstrate that naïve B cells form T-bet
pre-ASCs following stimulation with either Th1 cells or with IFNγ, IL-2, anti-Ig and TLR7/8 ligand and that IL-21 dependent ASC formation is significantly enhanced by IFNγ or IFNγ-producing T cells. IFNγ promotes ASC development by synergizing with IL-2 and TLR7/8 ligands to induce genome-wide epigenetic reprogramming of B cells, which results in increased chromatin accessibility surrounding IRF4 and BLIMP1 binding motifs and epigenetic remodeling of
and
loci. Finally, we show that IFNγ signals poise B cells to differentiate by increasing their responsiveness to IL-21. |
| format | Article |
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CD27
CD11c
CXCR5
(DN2) pre-antibody secreting cell (pre-ASC) subset. We demonstrate that naïve B cells form T-bet
pre-ASCs following stimulation with either Th1 cells or with IFNγ, IL-2, anti-Ig and TLR7/8 ligand and that IL-21 dependent ASC formation is significantly enhanced by IFNγ or IFNγ-producing T cells. IFNγ promotes ASC development by synergizing with IL-2 and TLR7/8 ligands to induce genome-wide epigenetic reprogramming of B cells, which results in increased chromatin accessibility surrounding IRF4 and BLIMP1 binding motifs and epigenetic remodeling of
and
loci. Finally, we show that IFNγ signals poise B cells to differentiate by increasing their responsiveness to IL-21.</description><identifier>EISSN: 2050-084X</identifier><identifier>PMID: 31090539</identifier><language>eng</language><publisher>England</publisher><subject>B-Lymphocyte Subsets - chemistry ; B-Lymphocyte Subsets - drug effects ; B-Lymphocyte Subsets - physiology ; Cell Differentiation ; Epigenesis, Genetic ; Gene Regulatory Networks ; Humans ; Interferon-gamma - metabolism ; Interleukins - metabolism ; Lupus Erythematosus, Systemic - pathology ; T-Box Domain Proteins - analysis ; Toll-Like Receptor 7 - metabolism ; Toll-Like Receptor 8 - metabolism</subject><ispartof>eLife, 2019-05, Vol.8</ispartof><rights>2019, Zumaquero et al.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><orcidid>0000-0002-7631-7114 ; 0000-0003-3083-1246 ; 0000-0002-1689-8148 ; 0000-0003-3926-0662 ; 0000-0001-7716-8504</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,780,784</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/31090539$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Zumaquero, Esther</creatorcontrib><creatorcontrib>Stone, Sara L</creatorcontrib><creatorcontrib>Scharer, Christopher D</creatorcontrib><creatorcontrib>Jenks, Scott A</creatorcontrib><creatorcontrib>Nellore, Anoma</creatorcontrib><creatorcontrib>Mousseau, Betty</creatorcontrib><creatorcontrib>Rosal-Vela, Antonio</creatorcontrib><creatorcontrib>Botta, Davide</creatorcontrib><creatorcontrib>Bradley, John E</creatorcontrib><creatorcontrib>Wojciechowski, Wojciech</creatorcontrib><creatorcontrib>Ptacek, Travis</creatorcontrib><creatorcontrib>Danila, Maria I</creatorcontrib><creatorcontrib>Edberg, Jeffrey C</creatorcontrib><creatorcontrib>Bridges, Jr, S Louis</creatorcontrib><creatorcontrib>Kimberly, Robert P</creatorcontrib><creatorcontrib>Chatham, W Winn</creatorcontrib><creatorcontrib>Schoeb, Trenton R</creatorcontrib><creatorcontrib>Rosenberg, Alexander F</creatorcontrib><creatorcontrib>Boss, Jeremy M</creatorcontrib><creatorcontrib>Sanz, Ignacio</creatorcontrib><creatorcontrib>Lund, Frances E</creatorcontrib><title>IFNγ induces epigenetic programming of human T-bet hi B cells and promotes TLR7/8 and IL-21 induced differentiation</title><title>eLife</title><addtitle>Elife</addtitle><description>Although B cells expressing the IFNγR or the IFNγ-inducible transcription factor T-bet promote autoimmunity in Systemic Lupus Erythematosus (SLE)-prone mouse models, the role for IFNγ signaling in human antibody responses is unknown. We show that elevated levels of IFNγ in SLE patients correlate with expansion of the T-bet expressing IgD
CD27
CD11c
CXCR5
(DN2) pre-antibody secreting cell (pre-ASC) subset. We demonstrate that naïve B cells form T-bet
pre-ASCs following stimulation with either Th1 cells or with IFNγ, IL-2, anti-Ig and TLR7/8 ligand and that IL-21 dependent ASC formation is significantly enhanced by IFNγ or IFNγ-producing T cells. IFNγ promotes ASC development by synergizing with IL-2 and TLR7/8 ligands to induce genome-wide epigenetic reprogramming of B cells, which results in increased chromatin accessibility surrounding IRF4 and BLIMP1 binding motifs and epigenetic remodeling of
and
loci. Finally, we show that IFNγ signals poise B cells to differentiate by increasing their responsiveness to IL-21.</description><subject>B-Lymphocyte Subsets - chemistry</subject><subject>B-Lymphocyte Subsets - drug effects</subject><subject>B-Lymphocyte Subsets - physiology</subject><subject>Cell Differentiation</subject><subject>Epigenesis, Genetic</subject><subject>Gene Regulatory Networks</subject><subject>Humans</subject><subject>Interferon-gamma - metabolism</subject><subject>Interleukins - metabolism</subject><subject>Lupus Erythematosus, Systemic - pathology</subject><subject>T-Box Domain Proteins - analysis</subject><subject>Toll-Like Receptor 7 - metabolism</subject><subject>Toll-Like Receptor 8 - metabolism</subject><issn>2050-084X</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2019</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNqFjk0KwjAUhIMgKtoryLtAMbUttltFURAX0oU7SZvX-qRJS5IuPJf38Ez-oGtnMzB8M0yPjeY85j5PotOQedZe-UuLKEmCdMCGYcBTHofpiLnd5vC4A2nZFWgBW6pQo6MCWtNURihFuoKmhEunhIbMz9HBhWAJBda1BaHlm1SNe7Wz_XExSz7Zbu_Pg--sBElliQa1I-Go0RPWL0Vt0fv6mE0362y19dsuVyjPrSElzO38uxn-BZ4wnUjl</recordid><startdate>20190515</startdate><enddate>20190515</enddate><creator>Zumaquero, Esther</creator><creator>Stone, Sara L</creator><creator>Scharer, Christopher D</creator><creator>Jenks, Scott A</creator><creator>Nellore, Anoma</creator><creator>Mousseau, Betty</creator><creator>Rosal-Vela, Antonio</creator><creator>Botta, Davide</creator><creator>Bradley, John E</creator><creator>Wojciechowski, Wojciech</creator><creator>Ptacek, Travis</creator><creator>Danila, Maria I</creator><creator>Edberg, Jeffrey C</creator><creator>Bridges, Jr, S Louis</creator><creator>Kimberly, Robert P</creator><creator>Chatham, W Winn</creator><creator>Schoeb, Trenton R</creator><creator>Rosenberg, Alexander F</creator><creator>Boss, Jeremy M</creator><creator>Sanz, Ignacio</creator><creator>Lund, Frances E</creator><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><orcidid>https://orcid.org/0000-0002-7631-7114</orcidid><orcidid>https://orcid.org/0000-0003-3083-1246</orcidid><orcidid>https://orcid.org/0000-0002-1689-8148</orcidid><orcidid>https://orcid.org/0000-0003-3926-0662</orcidid><orcidid>https://orcid.org/0000-0001-7716-8504</orcidid></search><sort><creationdate>20190515</creationdate><title>IFNγ induces epigenetic programming of human T-bet hi B cells and promotes TLR7/8 and IL-21 induced differentiation</title><author>Zumaquero, Esther ; Stone, Sara L ; Scharer, Christopher D ; Jenks, Scott A ; Nellore, Anoma ; Mousseau, Betty ; Rosal-Vela, Antonio ; Botta, Davide ; Bradley, John E ; Wojciechowski, Wojciech ; Ptacek, Travis ; Danila, Maria I ; Edberg, Jeffrey C ; Bridges, Jr, S Louis ; Kimberly, Robert P ; Chatham, W Winn ; Schoeb, Trenton R ; Rosenberg, Alexander F ; Boss, Jeremy M ; Sanz, Ignacio ; Lund, Frances E</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-pubmed_primary_310905393</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2019</creationdate><topic>B-Lymphocyte Subsets - chemistry</topic><topic>B-Lymphocyte Subsets - drug effects</topic><topic>B-Lymphocyte Subsets - physiology</topic><topic>Cell Differentiation</topic><topic>Epigenesis, Genetic</topic><topic>Gene Regulatory Networks</topic><topic>Humans</topic><topic>Interferon-gamma - metabolism</topic><topic>Interleukins - metabolism</topic><topic>Lupus Erythematosus, Systemic - pathology</topic><topic>T-Box Domain Proteins - analysis</topic><topic>Toll-Like Receptor 7 - metabolism</topic><topic>Toll-Like Receptor 8 - metabolism</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Zumaquero, Esther</creatorcontrib><creatorcontrib>Stone, Sara L</creatorcontrib><creatorcontrib>Scharer, Christopher D</creatorcontrib><creatorcontrib>Jenks, Scott A</creatorcontrib><creatorcontrib>Nellore, Anoma</creatorcontrib><creatorcontrib>Mousseau, Betty</creatorcontrib><creatorcontrib>Rosal-Vela, Antonio</creatorcontrib><creatorcontrib>Botta, Davide</creatorcontrib><creatorcontrib>Bradley, John E</creatorcontrib><creatorcontrib>Wojciechowski, Wojciech</creatorcontrib><creatorcontrib>Ptacek, Travis</creatorcontrib><creatorcontrib>Danila, Maria I</creatorcontrib><creatorcontrib>Edberg, Jeffrey C</creatorcontrib><creatorcontrib>Bridges, Jr, S Louis</creatorcontrib><creatorcontrib>Kimberly, Robert P</creatorcontrib><creatorcontrib>Chatham, W Winn</creatorcontrib><creatorcontrib>Schoeb, Trenton R</creatorcontrib><creatorcontrib>Rosenberg, Alexander F</creatorcontrib><creatorcontrib>Boss, Jeremy M</creatorcontrib><creatorcontrib>Sanz, Ignacio</creatorcontrib><creatorcontrib>Lund, Frances E</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><jtitle>eLife</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Zumaquero, Esther</au><au>Stone, Sara L</au><au>Scharer, Christopher D</au><au>Jenks, Scott A</au><au>Nellore, Anoma</au><au>Mousseau, Betty</au><au>Rosal-Vela, Antonio</au><au>Botta, Davide</au><au>Bradley, John E</au><au>Wojciechowski, Wojciech</au><au>Ptacek, Travis</au><au>Danila, Maria I</au><au>Edberg, Jeffrey C</au><au>Bridges, Jr, S Louis</au><au>Kimberly, Robert P</au><au>Chatham, W Winn</au><au>Schoeb, Trenton R</au><au>Rosenberg, Alexander F</au><au>Boss, Jeremy M</au><au>Sanz, Ignacio</au><au>Lund, Frances E</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>IFNγ induces epigenetic programming of human T-bet hi B cells and promotes TLR7/8 and IL-21 induced differentiation</atitle><jtitle>eLife</jtitle><addtitle>Elife</addtitle><date>2019-05-15</date><risdate>2019</risdate><volume>8</volume><eissn>2050-084X</eissn><abstract>Although B cells expressing the IFNγR or the IFNγ-inducible transcription factor T-bet promote autoimmunity in Systemic Lupus Erythematosus (SLE)-prone mouse models, the role for IFNγ signaling in human antibody responses is unknown. We show that elevated levels of IFNγ in SLE patients correlate with expansion of the T-bet expressing IgD
CD27
CD11c
CXCR5
(DN2) pre-antibody secreting cell (pre-ASC) subset. We demonstrate that naïve B cells form T-bet
pre-ASCs following stimulation with either Th1 cells or with IFNγ, IL-2, anti-Ig and TLR7/8 ligand and that IL-21 dependent ASC formation is significantly enhanced by IFNγ or IFNγ-producing T cells. IFNγ promotes ASC development by synergizing with IL-2 and TLR7/8 ligands to induce genome-wide epigenetic reprogramming of B cells, which results in increased chromatin accessibility surrounding IRF4 and BLIMP1 binding motifs and epigenetic remodeling of
and
loci. Finally, we show that IFNγ signals poise B cells to differentiate by increasing their responsiveness to IL-21.</abstract><cop>England</cop><pmid>31090539</pmid><orcidid>https://orcid.org/0000-0002-7631-7114</orcidid><orcidid>https://orcid.org/0000-0003-3083-1246</orcidid><orcidid>https://orcid.org/0000-0002-1689-8148</orcidid><orcidid>https://orcid.org/0000-0003-3926-0662</orcidid><orcidid>https://orcid.org/0000-0001-7716-8504</orcidid></addata></record> |
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| source | MEDLINE; DOAJ Directory of Open Access Journals; PubMed Central Open Access; EZB-FREE-00999 freely available EZB journals; PubMed Central |
| subjects | B-Lymphocyte Subsets - chemistry B-Lymphocyte Subsets - drug effects B-Lymphocyte Subsets - physiology Cell Differentiation Epigenesis, Genetic Gene Regulatory Networks Humans Interferon-gamma - metabolism Interleukins - metabolism Lupus Erythematosus, Systemic - pathology T-Box Domain Proteins - analysis Toll-Like Receptor 7 - metabolism Toll-Like Receptor 8 - metabolism |
| title | IFNγ induces epigenetic programming of human T-bet hi B cells and promotes TLR7/8 and IL-21 induced differentiation |
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