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

Abstract

Background 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. Methods To determine the impact of dysregulated regulatory T cells (Tregs), TFR 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 TFH-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 TFR cells promoted Ab production, activation of CNS CD11b+ cells, and EAE. Conclusions Blimp1 is essential for the maintenance of TFR cells and Ab responses in EAE. Dysregulated TFR cells and Ab responses promote CNS autoimmunity.

Follicular Helper CD4+ T Cells, Follicular Regulatory CD4+ T Cells, and Inducible Costimulator and Their Roles in Multiple Sclerosis and Experimental Autoimmune Encephalomyelitis

“…Besides, adoptive transfer of TFH cells could enhance the disease severity and delay disease remission [ 90 ]. Interestingly, mice with a FOXP3-specific deletion of Blimp1 develop severe EAE and increased TFH-B-Ab response, while having increased frequency of TFR cells [ 104 ]. Most TFH cells were TFH17cells and expressed more IL-17A and GM-CSF, as well as CXCL13 in Prdm1 fl/fl FOXP3 Cre EAE mice [ 104 ].…”

“…Interestingly, mice with a FOXP3-specific deletion of Blimp1 develop severe EAE and increased TFH-B-Ab response, while having increased frequency of TFR cells [ 104 ]. Most TFH cells were TFH17cells and expressed more IL-17A and GM-CSF, as well as CXCL13 in Prdm1 fl/fl FOXP3 Cre EAE mice [ 104 ]. In contrary to WT TFR cells, Blimp1-deleted TFR cells were more encephalitogenic, reflecting dysregulated Ab response and EAE progression [ 104 ].…”

Lineage Reprogramming of Effector Regulatory T Cells in Cancer

“…Consistent with the finding that expression of Blimp1 in the thymus is very low and Blimp1 unlikely regulates early T-cell development ( 84 ), mice with a Treg-specific deletion of Blimp1 do not show overt autoimmune phenotype ( 34 , 35 ). However, Tregs from these mice are unstable with reduced Foxp3 expression and produce inflammatory cytokines after immunization, and these mice develop severe experimental autoimmune encephalitis (EAE) ( 34 , 35 , 68 ). At the peak of EAE, the presence of IL-6 activates the DNA methylating enzyme Dnmt3a, resulting in CNS2 methylation.…”

“…These unstable T FR cells prematurely migrate into the GC and differentiate into T FH -like cells, resulting in T FH and GC B-cell expansion along with increased antibody and autoantibody production. Furthermore, adoptive transfer of Blimp1-deficient T FR cells can promote pathogenesis associated with dysregulated GC responses ( 34 , 68 ). Taken together, these studies have revealed Blimp1 as a new and central regulator of eTreg and T FR lineage stability and suppressive capacity.…”

“…Our recent study has revealed the importance of Blimp1 in the regulation of eTreg/T FR stability and suppressive function under immune and autoimmune conditions ( 34 , 68 ). However, the specific impact of Blimp1 + eTregs on, and mechanisms of action within, tumors are not yet explored.…”