Dysregulated follicular regulatory T cells and antibody responses exacerbate experimental autoimmune encephalomyelitis
Lin Luo, Xianzhen Hu, Michael Dixon, Brandon J. Pope, Jonathan D. Leavenworth, Chander Raman, William Meador, Jianmei W. Leavenworth
Abstract
Abstract Background Follicular regulatory T (T FR ) cells are essential for the regulation of germinal center (GC) response and humoral self-tolerance. Dysregulated follicular helper T (T FH ) cell-GC-antibody (Ab) response secondary to dysfunctional T FR cells is the root of an array of autoimmune disorders. The contribution of T FR cells to the pathogenesis of multiple sclerosis (MS) and murine experimental autoimmune encephalomyelitis (EAE) remains largely unclear. Methods To determine the impact of dysregulated regulatory T cells (Tregs), T FR cells, and Ab responses on EAE, we compared the MOG-induced EAE in mice with a FoxP3-specific ablation of the transcription factor Blimp1 to control mice. In vitro co-culture assays were used to understand how Tregs and Ab regulate the activity of microglia and central nervous system (CNS)-infiltrating myeloid cells. Results Mice with a FoxP3-specific deletion of Blimp1 developed severe EAE and failed to recover compared to control mice, reflecting conversion of Tregs into interleukin (IL)-17A/granulocyte-macrophage colony-stimulating factor (GM-CSF)-producing effector T cells associated with increased T FH -Ab responses, more IgE deposition in the 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 T FR cells promoted Ab production, activation of CNS CD11b + cells, and EAE. Conclusions Blimp1 is essential for the maintenance of T FR cells and Ab responses in EAE. Dysregulated T FR cells and Ab responses promote CNS autoimmunity.