Letter abstract
Nature Medicine 14, 337 - 342 (2008)
Published online: 17 February 2008 | doi:10.1038/nm1715
Differential regulation of central nervous system autoimmunity by TH1 and TH17 cells
Ingunn M Stromnes1, Lauren M Cerretti1, Denny Liggitt2, Robert A Harris3 & Joan M Goverman1
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 (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 TH17: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.
- Department of Immunology, Box 357650, HSC H474B, 1959 NE Pacific Street, Seattle, Washington 98195, USA.
- Department of Comparative Medicine, Box 357190, University of Washington, 1959 NE Pacific Street, Seattle, Washington 98195, USA.
- Applied Immunology Group, Department of Clinical Neurosciences, Karolinska Institute, Solna, CMM, L8:04, 171 76 Stockholm, Sweden.
Correspondence to: Joan M Goverman1 e-mail: goverman@u.washington.edu