Multiple sclerosis is an inflammatory, demyelinating disease of the central nervous system (CNS) characterized by a wide range of clinical signs. 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 inflammation. We demonstrate that T cells that are specific for different myelin epitopes generate populations characterized by different T helper type 17 (TH17) to T helper type 1 (TH1) ratios depending on the functional avidity of interactions between TCR and peptide-MHC complexes. Notably, the TH17:TH1 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:TH1 ratio. However, T cell infiltration and inflammation in the brain parenchyma occurs only when TH17 cells outnumber TH1 cells and trigger a disproportionate increase in interleukin-17 expression in the brain. In contrast, T cells showing a wide range of TH17:TH1 ratios induce spinal cord parenchymal inflammation. These findings reveal critical differences in the regulation of inflammation in the brain and spinal cord.
Bibliographical noteFunding Information:
We thank S. Levin at ZymoGenetics, Inc. for the IL17RA-Fc protein, H. Simkins and N. Mausolf for technical support and animal husbandry, D. Goverman, L. Kicknosway and R. Rowe for assistance with immunohistochemistry, R. Ransohoff for helpful discussions, T. Brabb, L. Castelli, Q. Ji, H. Simkins and A. Weinmann for critical reading of the manuscript, and B. Teeple for assistance with statistical analyses. This work was supported by the National Multiple Sclerosis Society (RG 3851-A-5 to J.M.G.) and the US National Institutes of Health (AI072737 to J.M.G.) and Public Health Service (T32-CA009537 to I.M.S.).