CCR6+Th cells in the cerebrospinal fluid of persons with multiple sclerosis are dominated by pathogenic non-classic Th1 cells and GM-CSF-only-secreting Th cells.
Considerable attention has been given to CCR6+IL-17-secreting CD4+T cells (Th17) in the pathology of a number of autoimmune diseases including multiple sclerosis (MS). However, other Th subsets also play important pathogenic roles, including those that secrete IFNγ and GM-CSF. CCR6 expression by Th17 cells allows their migration across the choroid plexus into the cerebrospinal fluid (CSF), where they are involved in the early phase of experimental autoimmune encephalomyelitis (EAE), and in MS these cells are elevated in the CSF during relapses and contain high frequencies of autoreactive cells. However, the relatively low frequency of Th17 cells suggests they cannot by themselves account for the high percentage of CCR6+cells in MS CSF. Here we identify the dominant CCR6+T cell subsets in both the blood and CSF as non-classic Th1 cells, including many that secrete GM-CSF, a key encephalitogenic cytokine. In addition, we show that Th cells secreting GM-CSF but not IFNγ or IL-17, a subset termed GM-CSF-only-secreting Th cells, also accumulate in the CSF. Importantly, in MS the proportion of IFNγ- and GM-CSF-secreting T cells expressing CCR6 was significantly enriched in the CSF, and was elevated in MS, suggesting these cells play a pathogenic role in this disease.
Centre for Translational Inflammation Research, Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK.
S M
SM
Restorick
Centre for Translational Inflammation Research, Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK.
L
L
Durant
Centre for Translational Inflammation Research, Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK; Neurology Department, University Hospital North Midlands, Stoke-on-Trent ST4 6QG, UK.
S
S
Kalra
Centre for Translational Inflammation Research, Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK.
G
G
Hassan-Smith
Centre for Translational Inflammation Research, Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK.
E
E
Rathbone
Centre for Translational Inflammation Research, Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK; Department of Neurology, Dudley Group NHS Foundation Trust, Russells Hall Hospital, Dudley DY1 2HQ, UK; School of Life and Health Sciences, Aston University, Birmingham B4 7ET, UK.
M R
MR
Douglas
Centre for Translational Inflammation Research, Institute of Inflammation and Ageing, College of Medical and Dental Sciences, University of Birmingham, Birmingham B15 2TT, UK. Electronic address: s.j.curnow@bham.ac.uk.
S J
SJ
Curnow
D000328:Adult; D000368:Aged; D015704:CD4 Antigens / Q000378:metabolism; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000378:metabolism*; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000097:blood / Q000134:cerebrospinal fluid* / Q000276:immunology; D054399:Receptors, CCR6 / Q000097:blood / Q000378:metabolism*; D018417:Th1 Cells / Q000378:metabolism*; D058504:Th17 Cells / Q000378:metabolism
C106311:CCR6 protein, human; D015704:CD4 Antigens; D054399:Receptors, CCR6; D007371:Interferon-gamma; D016178:Granulocyte-Macrophage Colony-Stimulating Factor
CCR6; Cerebrospinal fluid; GM-CSF; Multiple sclerosis; T cells; Th1; Th17