Interleukin 27 limits autoimmune encephalomyelitis by suppressing the development of interleukin 17-producing T cells.
Interleukin 27 (IL-27) was first characterized as a proinflammatory cytokine with T helper type 1-inducing activity. However, subsequent work has demonstrated that mice deficient in IL-27 receptor (IL-27R alpha) show exacerbated inflammatory responses to a variety of challenges, suggesting that IL-27 has important immunoregulatory functions in vivo. Here we demonstrate that IL-27R alpha-deficient mice were hypersusceptible to experimental autoimmune encephalomyelitis and generated more IL-17-producing T helper cells. IL-27 acted directly on effector T cells to suppress the development of IL-17-producing T helper cells mediated by IL-6 and transforming growth factor-beta. This suppressive activity was dependent on the transcription factor STAT1 and was independent of interferon-gamma. Finally, IL-27 suppressed IL-6-mediated T cell proliferation. These data provide a mechanistic explanation for the IL-27-mediated immune suppression noted in several in vivo models of inflammation.
Batten
Marcel
M
Department of Molecular Biology, Genentech, South San Francisco, California 94080, USA.
Li
Ji
J
Yi
Sothy
S
Kljavin
Noelyn M
NM
Danilenko
Dimitry M
DM
Lucas
Sophie
S
Lee
James
J
de Sauvage
Frederic J
FJ
Ghilardi
Nico
N
D000818:Animals; D002490:Central Nervous System / Q000276:immunology / Q000473:pathology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D007108:Immune Tolerance / Q000235:genetics / Q000276:immunology; D007371:Interferon-gamma / Q000378:metabolism; D020381:Interleukin-17 / Q000096:biosynthesis* / Q000235:genetics; D015850:Interleukin-6 / Q000494:pharmacology; D007378:Interleukins / Q000494:pharmacology / Q000502:physiology*; D008198:Lymph Nodes / Q000276:immunology; D008213:Lymphocyte Activation; D051379:Mice; D018345:Mice, Knockout; D018121:Receptors, Cytokine / Q000235:genetics*; D018123:Receptors, Interleukin; D050794:STAT1 Transcription Factor / Q000235:genetics / Q000378:metabolism; D006377:T-Lymphocytes, Helper-Inducer / Q000187:drug effects / Q000276:immunology*; D016212:Transforming Growth Factor beta / Q000494:pharmacology
C486767:Il27 protein, mouse; C484747:Il27ra protein, mouse; D020381:Interleukin-17; D015850:Interleukin-6; D007378:Interleukins; D018121:Receptors, Cytokine; D018123:Receptors, Interleukin; D050794:STAT1 Transcription Factor; C494080:Stat1 protein, mouse; D016212:Transforming Growth Factor beta; D007371:Interferon-gamma