Preferential recruitment of interferon-gamma-expressing TH17 cells in multiple sclerosis.
OBJECTIVE
There is substantial evidence supporting the role of interferon (IFN)-gamma-producing T helper (T(H)) 1 and interleukin (IL)-17-expressing T(H)17 lymphocytes in multiple sclerosis (MS) and its animal model, experimental allergic encephalomyelitis (EAE). However, to date little is known about the potential cooperative interplay between these 2 cytokines. In the current study, we sought to evaluate the frequency of IFN-gamma-expressing T(H)17 lymphocytes in MS and EAE, and study their recruitment into the central nervous system (CNS).


METHODS
Human T(H)17 lymphocytes were expanded in vitro from the blood of healthy controls and relapsing MS patients using IL-23. Immune cell migration to the CNS was assessed in vitro with primary cultures of human blood-brain barrier (BBB)-derived endothelial cells, and in vivo in EAE mice.


RESULTS
We demonstrate that in response to IL-23, human memory lymphocytes expand into a T(H)17 phenotype, with a subpopulation of cells simultaneously expressing IFN-gamma and IL-17. We note that lymphocytes obtained from the blood of relapsing MS patients have an increased propensity to expand into IFN-gamma-producing T(H)17 cells and identify numerous T lymphocytes coexpressing IL-17 and IFN-gamma in brain tissue of MS patients. We also find lymphocytes expressing both the T(H)1- and the T(H)17-associated transcription factors ROR gamma t and T-bet, in situ and in vitro. We further provide in vitro and in vivo evidence that IFN-gamma(+) T(H)17 lymphocytes preferentially cross the human BBB and accumulate in the CNS of mice during the effector phase of EAE.


CONCLUSIONS
Our data underscore the involvement of IFN-gamma(+) T(H)17 lymphocytes in the pathology of MS and EAE and their preferential recruitment into the CNS during inflammatory events.
Kebir
Hania
H
Neuroimmunology Research Unit, Center for Excellence in Neuromics, Montreal, Quebec, Canada.
Ifergan
Igal
I
Alvarez
Jorge Ivan
JI
Bernard
Monique
M
Poirier
Josée
J
Arbour
Nathalie
N
Duquette
Pierre
P
Prat
Alexandre
A
D000328:Adult; D000818:Animals; D001812:Blood-Brain Barrier / Q000276:immunology; D001921:Brain / Q000276:immunology*; D054443:Cell Migration Assays; D002464:Cell Migration Inhibition / Q000276:immunology; D002490:Central Nervous System / Q000276:immunology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000097:blood* / Q000276:immunology; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D007371:Interferon-gamma / Q000097:blood / Q000276:immunology*; D020381:Interleukin-17 / Q000276:immunology*; D053759:Interleukin-23 / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009103:Multiple Sclerosis / Q000097:blood* / Q000276:immunology; D020529:Multiple Sclerosis, Relapsing-Remitting / Q000097:blood / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D018417:Th1 Cells / Q000276:immunology; D018418:Th2 Cells / Q000276:immunology
D020381:Interleukin-17; D053759:Interleukin-23; D007371:Interferon-gamma