B Cell Intrinsic STING Signaling Is Not Required for Autoreactive Germinal Center Participation
Germinal centers (GCs) are induced microanatomical structures wherein B cells undergo affinity maturation to improve the quality of the antibody response. Although GCs are crucial to appropriate humoral responses to infectious challenges and vaccines, many questions remain about the molecular signal...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2021-12-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2021.782558/full |
| _version_ | 1819199374764277760 |
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| author | Kenneth Green Kenneth Green Thomas R. Wittenborn Cecilia Fahlquist-Hagert Ewa Terczynska-Dyla Nina van Campen Nina van Campen Lisbeth Jensen Line Reinert Rune Hartmann Søren R. Paludan Søren E. Degn |
| author_facet | Kenneth Green Kenneth Green Thomas R. Wittenborn Cecilia Fahlquist-Hagert Ewa Terczynska-Dyla Nina van Campen Nina van Campen Lisbeth Jensen Line Reinert Rune Hartmann Søren R. Paludan Søren E. Degn |
| author_sort | Kenneth Green |
| collection | DOAJ |
| description | Germinal centers (GCs) are induced microanatomical structures wherein B cells undergo affinity maturation to improve the quality of the antibody response. Although GCs are crucial to appropriate humoral responses to infectious challenges and vaccines, many questions remain about the molecular signals driving B cell participation in GC responses. The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is an important mediator of type I interferon and proinflammatory cytokine responses during infection and cellular stress. Recent studies have reported important roles for STING in B cell responses, including an impact on GC B cells and downstream antibody responses, which could have great consequences for vaccine design and understanding STING-associated interferonopathies. GCs are also involved in untoward reactions to autoantigens in a plethora of autoimmune disorders, and it is generally thought that these responses coopt the mechanisms used in foreign antigen-directed GCs. Here, we set out to investigate the importance of the cGAS-STING pathway in autoreactive B cell responses. In a direct competition scenario in a murine mixed bone marrow chimera model of autoreactive GCs, we find that B cell intrinsic deficiency of cGAS, STING, or the type I interferon receptor IFNAR, does not impair GC participation, whereas Toll-like receptor (TLR)-7 deficiency mediates a near-complete block. Our findings suggest that physiological B cell responses are strictly sustained by signals linked to BCR-mediated endocytosis. This wiring of B cell signals may enable appropriate antibody responses, while at the same time restricting aberrant antibody responses during infections and in autoimmune or autoinflammatory settings. |
| first_indexed | 2024-12-23T03:15:20Z |
| format | Article |
| id | doaj.art-77b01b2e96434180a61beee28b79cace |
| institution | Directory Open Access Journal |
| issn | 1664-3224 |
| language | English |
| last_indexed | 2024-12-23T03:15:20Z |
| publishDate | 2021-12-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Immunology |
| spelling | doaj.art-77b01b2e96434180a61beee28b79cace2022-12-21T18:02:07ZengFrontiers Media S.A.Frontiers in Immunology1664-32242021-12-011210.3389/fimmu.2021.782558782558B Cell Intrinsic STING Signaling Is Not Required for Autoreactive Germinal Center ParticipationKenneth Green0Kenneth Green1Thomas R. Wittenborn2Cecilia Fahlquist-Hagert3Ewa Terczynska-Dyla4Nina van Campen5Nina van Campen6Lisbeth Jensen7Line Reinert8Rune Hartmann9Søren R. Paludan10Søren E. Degn11Department of Biomedicine, Aarhus University, Aarhus, DenmarkDepartment of Molecular Biology and Genetics, Aarhus University, Aarhus, DenmarkDepartment of Biomedicine, Aarhus University, Aarhus, DenmarkDepartment of Biomedicine, Aarhus University, Aarhus, DenmarkDepartment of Biomedicine, Aarhus University, Aarhus, DenmarkDepartment of Biomedicine, Aarhus University, Aarhus, DenmarkDepartment of Biomedical Sciences, Radboud University Medical Center, Nijmegen, NetherlandsDepartment of Biomedicine, Aarhus University, Aarhus, DenmarkDepartment of Biomedicine, Aarhus University, Aarhus, DenmarkDepartment of Molecular Biology and Genetics, Aarhus University, Aarhus, DenmarkDepartment of Biomedicine, Aarhus University, Aarhus, DenmarkDepartment of Biomedicine, Aarhus University, Aarhus, DenmarkGerminal centers (GCs) are induced microanatomical structures wherein B cells undergo affinity maturation to improve the quality of the antibody response. Although GCs are crucial to appropriate humoral responses to infectious challenges and vaccines, many questions remain about the molecular signals driving B cell participation in GC responses. The cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) pathway is an important mediator of type I interferon and proinflammatory cytokine responses during infection and cellular stress. Recent studies have reported important roles for STING in B cell responses, including an impact on GC B cells and downstream antibody responses, which could have great consequences for vaccine design and understanding STING-associated interferonopathies. GCs are also involved in untoward reactions to autoantigens in a plethora of autoimmune disorders, and it is generally thought that these responses coopt the mechanisms used in foreign antigen-directed GCs. Here, we set out to investigate the importance of the cGAS-STING pathway in autoreactive B cell responses. In a direct competition scenario in a murine mixed bone marrow chimera model of autoreactive GCs, we find that B cell intrinsic deficiency of cGAS, STING, or the type I interferon receptor IFNAR, does not impair GC participation, whereas Toll-like receptor (TLR)-7 deficiency mediates a near-complete block. Our findings suggest that physiological B cell responses are strictly sustained by signals linked to BCR-mediated endocytosis. This wiring of B cell signals may enable appropriate antibody responses, while at the same time restricting aberrant antibody responses during infections and in autoimmune or autoinflammatory settings.https://www.frontiersin.org/articles/10.3389/fimmu.2021.782558/fullB cellsgerminal centersautoreactivityautoimmunitycGASSTING |
| spellingShingle | Kenneth Green Kenneth Green Thomas R. Wittenborn Cecilia Fahlquist-Hagert Ewa Terczynska-Dyla Nina van Campen Nina van Campen Lisbeth Jensen Line Reinert Rune Hartmann Søren R. Paludan Søren E. Degn B Cell Intrinsic STING Signaling Is Not Required for Autoreactive Germinal Center Participation Frontiers in Immunology B cells germinal centers autoreactivity autoimmunity cGAS STING |
| title | B Cell Intrinsic STING Signaling Is Not Required for Autoreactive Germinal Center Participation |
| title_full | B Cell Intrinsic STING Signaling Is Not Required for Autoreactive Germinal Center Participation |
| title_fullStr | B Cell Intrinsic STING Signaling Is Not Required for Autoreactive Germinal Center Participation |
| title_full_unstemmed | B Cell Intrinsic STING Signaling Is Not Required for Autoreactive Germinal Center Participation |
| title_short | B Cell Intrinsic STING Signaling Is Not Required for Autoreactive Germinal Center Participation |
| title_sort | b cell intrinsic sting signaling is not required for autoreactive germinal center participation |
| topic | B cells germinal centers autoreactivity autoimmunity cGAS STING |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2021.782558/full |
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