Autoreactive T cell activation is sufficient for breaking B cell tolerance in the setting of functional antigen-specific dominant tolerance (P4543)

Abstract

Abstract Systemic lupus erythematosus is a multisystem autoimmune disease characterized by anti-nuclear autoantibody (ANA) production by activated autoreactive B cells and the persistence and activation of autoreactive T cells. Animal models of lupus provide evidence that T and B cells interact to drive autoimmunity. Whether a break in tolerance in the T cell or B cell compartment could lead to a break in tolerance in the other compartment is unclear. Several studies have addressed this issue using transgenic autoreactive B cells, but whether significant elaboration of autoreactive B cells in the normal repertoire can be driven by activated T cells has not been shown. To address this question, we developed a mouse model in which naïve or activated transgenic autoreactive CD4+ T cells are transferred into hosts expressing their cognate pseudo-autoantigen (autoAg) on B cells and other antigen presenting cells (APCs). Interestingly, autoAg-specific Th1 or Th2 cells, but not naïve cells, drive ANA production by endogenous autoreactive B cells. In bone marrow chimeras, autoAg expression by radioresistant APCs was crucial for sufficient suppression of B cell activation by activated T cells. Additonally, we found that radioresistant APCs most effectively activate autoAg-specific splenic Tregs. We have shown that T cell activation is an important checkpoint in the prevention of ANA production by autoreactive B cells and that antigen-specific Tregs most effectively control ANA production.