Abstract
Abstract Tumor necrosis factor-α (TNF) antagonism has improved the treatment of autoimmune disorders including rheumatoid arthritis and inflammatory bowel disease but is contraindicated in multiple sclerosis (MS) due to disease exacerbation. The mechanisms underlying these contrasting responses remain elusive. The objective of this study was to investigate the effect of selective TNFR2 ablation on the autoreactivity of myelin oligodendrocyte glycoprotein (MOG)-specific T cells. We report that 92% of female C57BL/6 TNFR2-/- MOG-specific (2D2) TCR transgenic mice spontaneously develop experimental autoimmune encephalomyelitis (EAE); whereas, only 8% of male TNFR2-/- 2D2 littermates developed an autoimmune phenotype. Demyelination accompanied B cell and CD4 T cell infiltration in the spinal cords and optic nerves of TNFR2-/- 2D2 mice with EAE. CNS inflammation in these mice correlated with increased production of IFN-γ and IL-17 and elevated sera titers of MOG35-55-specific IgG2b. Ex vivo co-culture studies demonstrated autonomous TNFR2-/- 2D2 CD4 FoxP3+ regulatory T cell (Treg) dysfunction as well as increased resilience by FoxP3-/- 2D2 CD4 T cells to respond to Treg suppression. These results suggest that TNFR2 plays a key role in the functional tolerance of MOG-specific CD4 T and B cells in a sex-related manner. This novel spontaneous autoimmune model provides a unique paradigm to study T and B cell interactions as well as sex-related factors in multiple sclerosis susceptibility.
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