Dysregulated follicular regulatory T cells and antibody responses exacerbate CNS autoimmunity

Abstract

Abstract Follicular regulatory T (TFR) cells are essential for the regulation of germinal center (GC) response and humoral self-tolerance. Dysregulated follicular helper T (TFH) cell-GC-antibody (Ab) response secondary to dysfunctional TFR cells is the root of an array of autoimmune disorders. The contribution of TFR cells to the pathogenesis of multiple sclerosis (MS) and murine experimental autoimmune encephalomyelitis (EAE) remains largely unclear. Here we show that mice with a FoxP3-specific ablation of the transcription factor Blimp1 developed severe EAE and failed to recover compared to control mice, reflecting conversion of unstable regulatory T cells (Tregs) into IL-17A/GM-CSF-producing effector T-cells associated with increased TFH-Ab responses, more IgE deposition in the central nervous system (CNS) and inability to regulate CNS CD11b+ myeloid cells. Notably, serum IgE titers were positively correlated with EAE scores, and culture of CNS CD11b+ cells with sera from these EAE mice enhanced their activation, while transfer of Blimp1-deficient TFR cells promoted Ab production, activation of CNS CD11b+ cells and EAE. Moreover, compared to healthy controls, a small group of MS patients had fewer circulating Tregs and TFR cells that expressed reduced levels of Blimp1, associated with elevated serum IgE. These findings suggest that Blimp1 is essential for the maintenance of TFR cells and Ab responses in EAE, and that dysregulated TFR cells and Ab responses promote CNS autoimmunity.