Differential regulation of central nervous system autoimmunity by T(H)1 and T(H)17 cells.
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 (T(H)17) to T helper type 1 (T(H)1) ratios depending on the functional avidity of interactions between TCR and peptide-MHC complexes. Notably, the T(H)17:T(H)1 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(H)17:T(H)1 ratio. However, T cell infiltration and inflammation in the brain parenchyma occurs only when T(H)17 cells outnumber T(H)1 cells and trigger a disproportionate increase in interleukin-17 expression in the brain. In contrast, T cells showing a wide range of T(H)17:T(H)1 ratios induce spinal cord parenchymal inflammation. These findings reveal critical differences in the regulation of inflammation in the brain and spinal cord.
Stromnes
Ingunn M
IM
Department of Immunology, Box 357650, HSC H474B, 1959 NE Pacific Street, Seattle, Washington 98195, USA.
Cerretti
Lauren M
LM
Liggitt
Denny
D
Harris
Robert A
RA
Goverman
Joan M
JM
D000818:Animals; D015551:Autoimmunity / Q000276:immunology*; D001921:Brain / Q000166:cytology / Q000378:metabolism; D002490:Central Nervous System / Q000166:cytology / Q000276:immunology*; D000939:Epitopes / Q000276:immunology / Q000378:metabolism; D005786:Gene Expression Regulation; D051379:Mice; D008815:Mice, Inbred Strains; D013047:Specific Pathogen-Free Organisms; D013116:Spinal Cord / Q000166:cytology / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology*
D000939:Epitopes