Th17 central memory T cells are reduced by FTY720 in patients with multiple sclerosis.
OBJECTIVE
FTY720 is a sphingosine 1-phosphate (S1P) receptor modulator that showed efficacy in phase II and III clinical trials in patients with multiple sclerosis (MS). FTY720 inhibits lymphocyte egress from secondary lymphoid organs into the peripheral circulation, thereby reducing the number of circulating naïve and central memory T cells, but not effector memory T cells in blood. Little is known to which of these memory T-cell subsets interleukin 17 (IL-17)-producing T cells (Th17 cells) belong, which are considered to be key mediators of inflammation in MS, and how they are affected by treatment with FTY720. In this study, we determined the phenotype and frequency of Th17 cells in blood of untreated, FTY720-treated, and interferon-beta (IFNbeta)-treated patients with MS and healthy donors.


METHODS
In a prospective observational study, circulating T cells were phenotypically characterized and Th17 cells enumerated in T-cell subsets ex vivo. Production of IL-17 upon activation and expression of the Th17-specific transcription factor RORC2 was assessed in vitro.


RESULTS
Th17 cells were found primarily within central memory T cells in all study populations. FTY720 treatment reduced blood central memory T cells, including RORC2+ and IL-17-producing T cells, by >90%. FTY720 did not per se affect IL-17 production when added to activated T cells in vitro.


CONCLUSIONS
Phenotypic Th17 cells are defined by a central memory T-cell phenotype. FTY720 reduces these Th17 cells in blood. This is presumably because central memory T cells are retained by FTY720 in secondary lymphoid organs.
Mehling
M
M
Department of Neurology, University Hospitals Basel, Petersgraben 4, CH-4031 Basel, Switzerland.
Lindberg
R
R
Raulf
F
F
Kuhle
J
J
Hess
C
C
Kappos
L
L
Brinkmann
V
V
D000328:Adult; D017252:CD3 Complex / Q000378:metabolism; D015704:CD4 Antigens / Q000378:metabolism; D016022:Case-Control Studies; D017322:Clinical Trials, Phase II as Topic; D017326:Clinical Trials, Phase III as Topic; D004305:Dose-Response Relationship, Drug; D005260:Female; D000068876:Fingolimod Hydrochloride; D006801:Humans; D007155:Immunologic Factors / Q000627:therapeutic use; D007156:Immunologic Memory / Q000187:drug effects*; D007166:Immunosuppressive Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D016899:Interferon-beta / Q000627:therapeutic use; D020381:Interleukin-17 / Q000378:metabolism; D008297:Male; D009103:Multiple Sclerosis / Q000097:blood / Q000188:drug therapy* / Q000276:immunology*; D011409:Propylene Glycols / Q000008:administration & dosage / Q000627:therapeutic use*; D011446:Prospective Studies; D054398:Receptors, CCR4 / Q000378:metabolism; D054399:Receptors, CCR6 / Q000378:metabolism; D013110:Sphingosine / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000627:therapeutic use; D013601:T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism
C515354:CCR4 protein, human; C106311:CCR6 protein, human; D017252:CD3 Complex; D015704:CD4 Antigens; D007155:Immunologic Factors; D007166:Immunosuppressive Agents; D020381:Interleukin-17; D011409:Propylene Glycols; D054398:Receptors, CCR4; D054399:Receptors, CCR6; D016899:Interferon-beta; D000068876:Fingolimod Hydrochloride; D013110:Sphingosine