The role of tumor necrosis factor receptor 2 (TNFR2) in EAE

Abstract Multiple Sclerosis (MS) is a chronic autoimmune disease of the central nervous system which affects over 2 million people worldwide and is the most common neurological disability in young adults. MS is a heterogenous disease characterized by recurrent, remitting and/or progressive neurological deficits, and clinical manifestations include nerve damage, visual loss, motor and balance impairment, gait disturbance, and others. While several environmental and genetic risk factors have been identified, such as the DR2b (DRB1*1501) human MHC class II allele, the molecular mechanisms underlying the development and severity of MS remain poorly understood. Tumor necrosis factor is a cytokine that exerts its effects through two different surface receptors TNFR1 and TNFR2, and it has been identified as a key player in MS pathogenesis. TNFR2 is thought to have a protective role in experimental autoimmune encephalomyelitis (EAE), a mouse model for MS, by altering the function of astrocytes and regulatory T cells (Tregs). Previous data from our lab demonstrated that in the absence of TNFR2, transgenic mice expressing the DR2b allele and lacking mouse MHC class II (DR2bDR2) develop a more severe and progressive form of EAE, exhibiting astrogliosis. We have previously demonstrated that multiple Treg-associated genes were upregulated in CD4 +T cells from DR2bDR2 mice compared to those from control mice. However, the exact mechanism by which TNFR2 regulates Treg function in EAE is unknown. Here, we show that deletion of TNFR2 impacts the ability of Tregs to expand in vitro as well as their localization within the brains of mice undergoing EAE. Our results provide key insights into the mechanism by which TNFR2 limits and protects against CNS inflammation.