Contribution of the effector Treg-B-antibody nexus to the regulation of CNS autoimmunity

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PROJECT SUMMARY: Multiple sclerosis (MS) is a debilitating autoimmune inflammatory disease that affects the central nervous system (CNS), and experimental autoimmune encephalomyelitis (EAE) is the most commonly used animal model of MS. Although emerging data have suggested the contribution of TFR-TFH-GC B-antibody (Ab) responses to EAE and MS, the contribution of TFR cells to the disease pathogenesis and the nature of Ab response remain largely unknown. Effector Tregs (eTregs) including TFR cells must maintain their suppressive anergic phenotype at non-lymphoid tissues, including the CNS, and during ongoing inflammatory responses. However, the mechanisms that ensure maintenance of anergy, lineage identity and expression of regulatory activity by eTregs are not well defined. Our recent publication has revealed that expression of the transcription factor Blimp1 in eTregs, including the TFR subset, is essential for maintenance of FoxP3 expression and stable eTreg suppressive activity. The pro-inflammatory potential of Blimp1-deficient eTregs has prompted us to examine their impact on the CNS autoimmunity using the myelin oligodendrocyte glycoprotein (MOG)-induced EAE model. We observed that mice with a FoxP3-specific ablation of Blimp1 developed severe EAE, failed to recover and all succumbed to paralysis compared to controls, which reflected conversion of unstable Blimp1- deficient eTregs into IL-17A/GM-CSF-producing effector T-cells (Teff) associated with enhanced glycolysis and loss of suppression on TFH-Ab responses as well as aberrant microglial activation. Surprisingly, serum IgE titers were positively correlated with EAE scores and these mice had more IgE deposition in the CNS. Moreover, compared to healthy controls (HC), MS patients had reduced circulating Blimp1+ Tregs and TFR cells expressing lower levels of Blimp1 and IL-10, associated with elevated IgE levels. We hypothesize that Blimp1 expression enforces eTreg stability under CNS autoimmunity by preventing acquisition of effector activity and metabolic skewing as well as restraining TFH-Ab response. Using combined transcriptomic, epigenomic and metabolic assays, we will delineate the mechanisms by which eTregs, TFR cells and Ab responses regulate neuroinflammation and how loss of Blimp1 in eTregs re-shape the CNS microenvironment. The proposed study will uncover Blimp1 as a new regulator that is important for eTreg stability and for mediating disease recovery during CNS autoimmunity. Our findings point to a previously unrecognized mechanism enforcing eTreg stability by coordinating response to the autoimmune milieu and maintaining metabolic fitness via regulation of Blimp1. This study also has the potential to reveal the unappreciated role of TFR cells, and to clarify the role of B-cells and Ab responses (particularly IgE) in the regulation of CNS autoimmunity. Insights from these studies may provide critical strategies to formulate novel therapeutic approaches to MS by exploiting a surprising aspect of the biology of a critical T-cell subset.