Differential regulation of central nervous system autoimmunity by T H1 and TH17 cells

Ingunn M. Stromnes, Lauren M. Cerretti, Denny Liggitt, Robert A. Harris, Joan M. Goverman

Research output: Contribution to journalArticlepeer-review

441 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)337-342
Number of pages6
JournalNature Medicine
Volume14
Issue number3
DOIs
StatePublished - Mar 1 2008
Externally publishedYes

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