B Cell Intrinsic STING Signaling Is Not Required for Autoreactive Germinal Center Participation

Kenneth Green; Thomas R. Wittenborn; Cecilia Fahlquist-Hagert; Ewa Terczynska-Dyla; Nina van Campen; Lisbeth Jensen; Line Reinert; Rune Hartmann; Søren R. Paludan; Søren E. Degn

doi:10.3389/fimmu.2021.782558

B Cell Intrinsic STING Signaling Is Not Required for Autoreactive Germinal Center Participation

Kenneth Green, Thomas R. Wittenborn, Cecilia Fahlquist-Hagert, Ewa Terczynska-Dyla, Nina van Campen, Lisbeth Jensen, Line Reinert, Rune Hartmann, Søren R. Paludan, Søren E. Degn^*

^*Corresponding author af dette arbejde

Publikation: Bidrag til tidsskrift/Konferencebidrag i tidsskrift /Bidrag til avis › Tidsskriftartikel › Forskning › peer review

3 Citationer (Scopus)

Abstract

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.

Originalsprog	Engelsk
Artikelnummer	782558
Tidsskrift	Frontiers in Immunology
Vol/bind	12
Antal sider	18
ISSN	1664-3224
DOI	https://doi.org/10.3389/fimmu.2021.782558
Status	Udgivet - dec. 2021

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10.3389/fimmu.2021.782558Licens: CC BY

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@article{e847d4932ee6494f8336891440fff0b9,

title = "B Cell Intrinsic STING Signaling Is Not Required for Autoreactive Germinal Center Participation",

abstract = "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.",

keywords = "autoimmunity, autoreactivity, B cells, cGAS, germinal centers, IFNAR, STING, TLR7",

author = "Kenneth Green and Wittenborn, {Thomas R.} and Cecilia Fahlquist-Hagert and Ewa Terczynska-Dyla and {van Campen}, Nina and Lisbeth Jensen and Line Reinert and Rune Hartmann and Paludan, {S{\o}ren R.} and Degn, {S{\o}ren E.}",

note = "Publisher Copyright: Copyright {\textcopyright} 2021 Green, Wittenborn, Fahlquist-Hagert, Terczynska-Dyla, van Campen, Jensen, Reinert, Hartmann, Paludan and Degn.",

year = "2021",

month = dec,

doi = "10.3389/fimmu.2021.782558",

language = "English",

volume = "12",

journal = "Frontiers in Immunology",

issn = "1664-3224",

publisher = "Frontiers Research Foundation",

}

TY - JOUR

T1 - B Cell Intrinsic STING Signaling Is Not Required for Autoreactive Germinal Center Participation

AU - Green, Kenneth

AU - Wittenborn, Thomas R.

AU - Fahlquist-Hagert, Cecilia

AU - Terczynska-Dyla, Ewa

AU - van Campen, Nina

AU - Jensen, Lisbeth

AU - Reinert, Line

AU - Hartmann, Rune

AU - Paludan, Søren R.

AU - Degn, Søren E.

PY - 2021/12

Y1 - 2021/12

N2 - 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.

AB - 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.

KW - autoimmunity

KW - autoreactivity

KW - B cells

KW - cGAS

KW - germinal centers

KW - IFNAR

KW - STING

KW - TLR7

UR - http://www.scopus.com/inward/record.url?scp=85121987634&partnerID=8YFLogxK

U2 - 10.3389/fimmu.2021.782558

DO - 10.3389/fimmu.2021.782558

M3 - Journal article

C2 - 34938294

AN - SCOPUS:85121987634

SN - 1664-3224

VL - 12

JO - Frontiers in Immunology

JF - Frontiers in Immunology

M1 - 782558

ER -

B Cell Intrinsic STING Signaling Is Not Required for Autoreactive Germinal Center Participation

Abstract

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