Dysregulated follicular regulatory T cells and antibody responses exacerbate experimental autoimmune...

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.

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.

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.

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.