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.

The extrafollicular response is sufficient to drive initiation of autoimmunity and early disease hallmarks of lupus

“…Uniquely to this model, the spontaneous autoreactive GCs established by the 564Igi compartment become populated and chronically self-sustained by the non-564Igi (WT) B cells and gain independence from the initial 564Igi trigger. From around six weeks after reconstitution, GCs are almost exclusively (~95%) composed of WT-derived cells ( 11 , 22 ). Reconstitution with a third of each of 564Igi BM, BM from a wild-type donor, and BM from a donor harboring a specified genetic defect, results in chimeras with two equal-sized compartments of B cells sufficient or deficient in the gene of interest.…”

“…In the context of autoimmune diseases, initial B cell reactivities often target autoantigenic components that carry endogenous TLR ligands capable of stimulating them independently of T cells ( 8 – 10 ). These seem strictly limited to components topologically linked to the B cell receptor ( 11 ). Although TLR9 was originally reported to be a main driver of autoreactive B cell activation ( 10 ), more recent insights suggest RNA recognition through TLR7, and potentially TLR3, is the most important contributor to break-of-tolerance in B cells ( 9 , 12 , 13 ), with TLR9 playing a counterbalancing role ( 14 – 16 ).…”

Extrafollicular responses are sufficient to drive initiation of autoimmunity and early disease hallmarks of lupus

“…Uniquely to this model, the spontaneous autoreactive GCs established by the 564Igi compartment become populated and chronically self-sustained by the non-564Igi (WT) B cells and gain independence from the initial 564Igi trigger. From around six weeks after reconstitution, GCs are almost exclusively (~95%) composed of WT-derived cells (Degn, van der Poel, Firl, et al, 2017;Green et al, 2021). Reconstitution with a third of each of 564Igi BM, BM from a wild-type donor, and BM from a donor harboring a specified genetic defect, hence results in chimeras with two equal-sized compartments of B cells sufficient or deficient in the gene of interest.…”

“…In the context of autoimmune diseases, it has been noted that initial B cell reactivities often target autoantigenic components that carry endogenous TLR ligands capable of stimulating them independently of T cells (Lau et al, 2005; Leadbetter et al, 2002; Sweet et al, 2011). Of note, these seem strictly limited to components topologically linked to the B cell receptor (Green et al, 2021). Interestingly, signals that drive initial B cell activation also seem to limit the extent of affinity maturation (Akkaya et al, 2018).…”