title: Functional inflammatory profiles distinguish myelin-reactive T cells from patients with multiple sclerosis.
abstract: Myelin-reactive T cells have been identified in patients with multiple sclerosis (MS) and healthy subjects with comparable frequencies, but the contribution of these autoreactive T cells to disease pathology remains unknown. A total of 13,324 T cell libraries generated from blood of 23 patients and 22 healthy controls were interrogated for reactivity to myelin antigens. Libraries derived from CCR6(+) myelin-reactive T cells from patients with MS exhibited significantly enhanced production of interferon-γ (IFN-γ), interleukin-17 (IL-17), and granulocyte-macrophage colony-stimulating factor (GM-CSF) compared to healthy controls. Single-cell clones isolated by major histocompatibility complex/peptide tetramers from CCR6(+) T cell libraries also secreted more proinflammatory cytokines, whereas clones isolated from controls secreted more IL-10. The transcriptomes of myelin-specific CCR6(+) T cells from patients with MS were distinct from those derived from healthy controls and, notably, were enriched in T helper cell 17 (TH17)-induced experimental autoimmune encephalitis gene signatures, and gene signatures derived from TH17 cells isolated other human autoimmune diseases. These data, although not causal, imply that functional differences between antigen-specific T cells from MS and healthy controls are fundamental to disease development and support the notion that IL-10 production from myelin-reactive T cells may act to limit disease progression or even pathogenesis.
authors.affiliation: Departments of Neurology and Immunobiology, Yale School of Medicine, New Haven, CT 06520, USA.
authors.forename: Yonghao
authors.initials: Y
authors.lastname: Cao
authors.affiliation: Department of Biological Engineering, Koch Institute for Integrative Cancer Research at Massachusetts Institute of Technology (MIT), Cambridge, MA 02139, USA.
authors.forename: Brittany A
authors.initials: BA
authors.lastname: Goods
authors.affiliation: Departments of Neurology and Immunobiology, Yale School of Medicine, New Haven, CT 06520, USA.
authors.forename: Khadir
authors.initials: K
authors.lastname: Raddassi
authors.affiliation: Benaroya Research Institute, Virginia Mason Research Center, Seattle, WA 98101, USA.
authors.forename: Gerald T
authors.initials: GT
authors.lastname: Nepom
authors.affiliation: Benaroya Research Institute, Virginia Mason Research Center, Seattle, WA 98101, USA. Department of Medicine, University of Washington, Seattle, WA 98101, USA.
authors.forename: William W
authors.initials: WW
authors.lastname: Kwok
authors.affiliation: Department of Chemical Engineering, Koch Institute for Integrative Cancer Research at MIT, Cambridge, MA 02139, USA. The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.
authors.forename: J Christopher
authors.initials: JC
authors.lastname: Love
authors.affiliation: Departments of Neurology and Immunobiology, Yale School of Medicine, New Haven, CT 06520, USA. The Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA. david.hafler@yale.edu.
authors.forename: David A
authors.initials: DA
authors.lastname: Hafler
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D005260:Female; D020869:Gene Expression Profiling; D006801:Humans; D007249:Inflammation / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000276:immunology*; D009186:Myelin Sheath / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*