Specific central nervous system recruitment of HLA-G(+) regulatory T cells in multiple sclerosis.
OBJECTIVE
We have recently described a novel population of natural regulatory T cells (T(reg)) that are characterized by the expression of HLA-G and may be found at sites of tissue inflammation (HLA-G(pos) T(reg)). Here we studied the role of these cells in multiple sclerosis (MS), a prototypic autoimmune inflammatory disorder of the central nervous system (CNS).


METHODS
Sixty-four patients with different types of MS, 9 patients with other neurological diseases, and 20 healthy donors were included in this study. Inflamed brain lesions from 5 additional untreated MS patients were examined. HLA-G(pos) T(reg) were analyzed in the cerebrospinal fluid (CSF) by flow cytometry and in inflammatory demyelinating lesions of MS brain specimens by immunohistochemistry. Functional capacity was accessed and transmigration was determined using an in vitro model of the human blood-brain barrier (BBB).


RESULTS
HLA-G(pos) T(reg) were found enriched in the inflamed CSF of MS patients and in inflammatory demyelinating lesions of MS brain specimens. HLA-G(pos) T(reg) showed a strong propensity to transmigrate across BBB, which was vigorously driven by inflammatory chemokines, and associated with a gain of suppressive capacity upon transmigration. CSF-derived HLA-G(pos) T(reg) of MS patients represented a population of activated central memory activated T cells with an upregulated expression of inflammatory chemokine receptors and exhibiting full suppressive capacity. Unlike natural FoxP3-expressing T(reg), HLA-G(pos) T(reg) derived from peripheral blood were functionally unimpaired in MS.


CONCLUSIONS
In MS, HLA-G(pos) T(reg) may serve to control potentially destructive immune responses directly at the sites of CNS inflammation and to counterbalance inflammation once specifically recruited to the CNS.
Huang
Yu-Hwa
YH
Department of Neurology, University of Würzburg, Würzburg, Germany.
Zozulya
Alla L
AL
Weidenfeller
Christian
C
Metz
Imke
I
Buck
Dorothea
D
Toyka
Klaus V
KV
Brück
Wolfgang
W
Wiendl
Heinz
H
D000328:Adult; D000368:Aged; D001812:Blood-Brain Barrier / Q000473:pathology / Q000503:physiopathology; D001921:Brain / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D002460:Cell Line; D002465:Cell Movement; D005260:Female; D005434:Flow Cytometry; D006680:HLA Antigens / Q000378:metabolism*; D059951:HLA-G Antigens; D015395:Histocompatibility Antigens Class I / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000276:immunology* / Q000473:pathology / Q000503:physiopathology; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D019713:Receptors, CCR5 / Q000378:metabolism; D018121:Receptors, Cytokine / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000502:physiology*; D055815:Young Adult
D006680:HLA Antigens; D059951:HLA-G Antigens; D015395:Histocompatibility Antigens Class I; D011948:Receptors, Antigen, T-Cell; D019713:Receptors, CCR5; D018121:Receptors, Cytokine