Differential regulation of central nervous system autoimmunity by TH1 and TH17 cells

Abstract

Multiple sclerosis is an inflammatory, demyelinating disease of the central nervous system (CNS) characterized by a wide range of clinical signs¹. The location of lesions in the CNS is variable and is a crucial determinant of clinical outcome. Multiple sclerosis is believed to be mediated by myelin-specific T cells, but the mechanisms that determine where T cells initiate inflammation are unknown. Differences in lesion distribution have been linked to the HLA complex, suggesting that T cell specificity influences sites of inflammation². We demonstrate that T cells that are specific for different myelin epitopes generate populations characterized by different T helper type 17 (T_H17) to T helper type 1 (T_H1) ratios depending on the functional avidity of interactions between TCR and peptide-MHC complexes. Notably, the T_H17:T_H1 ratio of infiltrating T cells determines where inflammation occurs in the CNS. Myelin-specific T cells infiltrate the meninges throughout the CNS, regardless of the T_H17:T_H1 ratio. However, T cell infiltration and inflammation in the brain parenchyma occurs only when T_H17 cells outnumber T_H1 cells and trigger a disproportionate increase in interleukin-17 expression in the brain. In contrast, T cells showing a wide range of T_H17:T_H1 ratios induce spinal cord parenchymal inflammation. These findings reveal critical differences in the regulation of inflammation in the brain and spinal cord.