Suppressive effect of IL-27 on encephalitogenic Th17 cells and the effector phase of experimental autoimmune encephalomyelitis.
IL-27 has been shown to play a suppressive role in experimental autoimmune encephalomyelitis (EAE) as demonstrated by more severe disease in IL-27R-deficient (WSX-1(-/-)) mice. However, whether IL-27 influences the induction or effector phase of EAE is unknown. This is an important question as therapies for autoimmune diseases are generally started after autoreactive T cells have been primed. In this study, we demonstrate maximal gene expression of IL-27 subunits and its receptor in the CNS at the effector phases of relapsing-remitting EAE including disease peak and onset of relapse. We also show that activated astrocyte cultures secrete IL-27p28 protein which is augmented by the endogenous factor, IFN-gamma. To investigate functional significance of a correlation between gene expression and disease activity, we examined the effect of IL-27 at the effector phase of disease using adoptive transfer EAE. Exogenous IL-27 potently suppressed the ability of encephalitogenic lymph node and spleen cells to transfer EAE. IL-27 significantly inhibited both nonpolarized and IL-23-driven IL-17 production by myelin-reactive T cells thereby suppressing their encephalitogenicity in adoptive transfer EAE. Furthermore, we demonstrate a strong suppressive effect of IL-27 on active EAE in vivo when delivered by s.c. osmotic pump. IL-27-treated mice had reduced CNS inflammatory infiltration and, notably, a lower proportion of Th17 cells. Together, these data demonstrate the suppressive effect of IL-27 on primed, autoreactive T cells, particularly, cells of the Th17 lineage. IL-27 can potently suppress the effector phase of EAE in vivo and, thus, may have therapeutic potential in autoimmune diseases such as multiple sclerosis.
Fitzgerald
Denise C
DC
Department of Neurology, Thomas Jefferson University, 900 Walnut Street, Philadelphia, PA 19107, USA.
Ciric
Bogoljub
B
Touil
Tarik
T
Harle
Heather
H
Grammatikopolou
Julia
J
Das Sarma
Jayasri
J
Gran
Bruno
B
Zhang
Guang-Xian
GX
Rostami
Abdolmohamad
A
D019264:Adoptive Transfer; D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000276:immunology; D002478:Cells, Cultured; D002490:Central Nervous System / Q000187:drug effects* / Q000276:immunology / Q000473:pathology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000276:immunology* / Q000473:pathology; D005260:Female; D015870:Gene Expression; D007165:Immunosuppression Therapy; D007371:Interferon-gamma / Q000494:pharmacology; D007378:Interleukins / Q000235:genetics / Q000494:pharmacology*; D008198:Lymph Nodes / Q000276:immunology; D051379:Mice; D015778:Minor Histocompatibility Antigens; D018121:Receptors, Cytokine / Q000235:genetics; D018123:Receptors, Interleukin; D012008:Recurrence; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects* / Q000276:immunology
C499601:Ebi3 protein, mouse; C486767:Il27 protein, mouse; C484747:Il27ra protein, mouse; D007378:Interleukins; D015778:Minor Histocompatibility Antigens; D018121:Receptors, Cytokine; D018123:Receptors, Interleukin; D007371:Interferon-gamma