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1709 A threshold of B cell costimulatory signals is required for spontaneous germinal center formation in autoimmunity
  1. Kristy Chiang1,
  2. Andrea D Largent1,
  3. Tanvi Arkatkar1,
  4. Christopher D Thouvenel1,
  5. Samuel W Du1,
  6. Natali Shumlak1,
  7. Jonathan Woods1,
  8. Quan-Zhen Li2,
  9. David J Rawlings1,3,4 and
  10. Shaun W Jackson1,4
  1. 1Seattle Children’s Research Institute, Seattle, WA
  2. 2Department of Immunology, University of Texas Southwestern Medical Center, Dallas, TX
  3. 3Department of Immunology
  4. 4Department of Pediatrics, University of Washington School of Medicine


Background Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease characterized by polyclonal B cell activation. Rather than being downstream targets of CD4+ T cell activation, B cells can initiate breaks in T cell tolerance by orchestrating the formation of spontaneous germinal centers (GC). Engagement of CD28 on CD4+ T cells with CD80/CD86 (B7.1/B7.2) on antigen presenting cells (APCs) is required for GC formation, but recent data suggest a limited role for B cell-intrinsic CD80/CD86 in this process (Watanabe, J Exp Med, 2017). However, whether B cell costimulatory signals are similarly redundant in immunization models vs. humoral autoimmunity is unclear, given differences in (auto)antigen abundance, affinity and adjuvant load.

Methods To determine whether B cell costimulatory signals modulate autoimmune GCs, we used a chimeric model of B cell-driven autoimmunity to contrast the impact of global CD28 and B cell-intrinsic CD80/CD86 deletion in humoral autoimmunity.

Results Whereas myeloid signals were critical for initial CD4+ T cell priming and CXCR5 upregulation, complete T follicular helper (Tfh) cell maturation required B cell-intrinsic CD80/CD86 expression. Surprisingly, loss of CD28 and B cell-intrinsic CD80/CD86 similarly abrogated the formation of spontaneous autoimmune GCs. Interestingly, absent GCs differentially impacted serum autoantibody (autoAb) titers. In keeping with distinct extra-follicular (EF) and GC activation pathways driving lupus autoAb, lack of GCs correlated with loss of RNA-associated autoAb but preserved anti-dsDNA and connective tissue antigen reactivity. These data suggest a prominent role for GC-independent B cell activation via an EF pathway in the genesis of diverse pathogenic autoAb in SLE. Finally, based on CTLA-4 haploinsufficiency promoting spontaneous humoral autoimmunity in humans, we tested whether modulating B cell CD80/CD86 levels impacts spontaneous GCs. Strikingly, heterozygous B cell CD80/CD86 deletion recapitulated the phenotype of complete deletion, resulting in lack of Tfh expansion, GC formation and generation of RNA-associated autoAb.

Conclusion Our data show that during initial interactions between antigen-primed, autoreactive T and B cells, a threshold of B cell costimulatory signals is required for T cell activation and spontaneous GC formation. In addition, our findings support a model in which both EF and GC activation pathways provide distinct contributions to the lupus autoAb repertoire. Loss of B cell costimulatory signals uniquely dissociates these events, by abrogating the formation of autoimmune GCs without preventing T cell-dependent EF B cell activation.

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