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

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

doi:10.3389/fimmu.2021.782558

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.

Highlights

Antibodies are an important constituent of the adaptive immune response
We set out to investigate the role of the cyclic GMP-AMP synthase (cGAS)-stimulator of interferon genes (STING) signal transduction pathway in autoreactive GCB cells using a murine mixed bone marrow (BM) chimera model that mimics the archetypal autoimmune disease Systemic Lupus Erythematosus (SLE) [37]
STING has been suggested to regulate cell death signaling in lymphocytes [45], and since a hallmark of GCB responses is rapid proliferation regulated by high rates of controlled apoptosis, we investigated if the degree of proliferating GCB cells varied between the compartments with either a sufficient or deficient STING function

Summary

Introduction

Antibodies are an important constituent of the adaptive immune response. During an ongoing response, antibodies are refined through a process called affinity maturation to attain high specificity and affinity against their cognate antigen. The selected B cell clones differentiate into either antibody producing plasma cells (PCs) or memory B cells This process contributes greatly to the efficiency, plasticity and versatility of the humoral immune response against foreign antigens [3]. The B cell pool expands and diversifies their antibody repertoire, which results in a diversification of the antigenic determinants targeted by the immune system. While this process is thought to contribute to robust protection against pathogens, it plays a central role in propagating autoreactivity [9, 10]. It has been noted that years before patients present with SLE, they evolve autoantibodies targeting an increasing breadth of autoantigens, and this is thought to drive the pathogenic process [11]

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