TY - JOUR

T1 - B7-H1 Selectively Controls TH17 Differentiation and Central Nervous System Autoimmunity via a Novel Non-PD-1-Mediated Pathway

AU - Herold, Martin

AU - Posevitz, Vilmos

AU - Chudyka, Daria

AU - Hucke, Stephanie

AU - Groß, Catharina

AU - Kurth, Frank

AU - Leder, Christoph

AU - Loser, Karin

AU - Kurts, Christian

AU - Knolle, Percy

AU - Klotz, Luisa

AU - Wiendl, Heinz

N1 - Copyright © 2015 by The American Association of Immunologists, Inc.

PY - 2015/10/15

Y1 - 2015/10/15

N2 - It is currently acknowledged that T H17 cells are critically involved in the pathogenesis of autoimmune diseases such as multiple sclerosis (MS). In this article, we demonstrate that signals delivered by the coinhibitory molecule B7-homologue 1 (B7-H1) via a B7-homologue 1 mouse-IgG2aFc (B7-H1-Ig) fusion protein nearly abolish T H17, but not T H1 and T H2, differentiation via direct interaction with the T cell. These effects were equally pronounced in the absence of programmed death-1 or B7.1 and B7.2 on the T cell side, thus providing clear evidence that B7-H1 modulates T cell differentiation via a novel receptor. Mechanistically, B7-H1 interfered with early TCR-mediated signaling and cytokine-mediated induction of the T H17-determining transcription factors retinoic acid-related orphan receptor g t and IFN regulator factor-4 in a programmed death-1 and B7-independent fashion. In an animal model of MS, active myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis, B7-H1-Ig exhibited a significant and long-lasting effect on disease severity upon administration during the first 5 d of the priming phase, which was accompanied by reduced T H17 responses in the periphery and within the CNS. Importantly, B7-H1-Ig was even capable of interfering with T cell encephalitogenicity when interaction with the T cells occurred after priming using an adoptive transfer experimental autoimmune encephalomyelitis model. In line with this, both naive human CD4 + T cells and differentiated T H17 effector cells from MS patients were highly sensitive toward B7-H1-Ig-mediated T H17 suppression. Together, we propose the existence of a novel B7-H1-mediated immune-regulatory pathway in T cells, which selectively limits murine and human T H17 cell responses and might be therapeutically exploited to control T H17-mediated autoimmunity.

AB - It is currently acknowledged that T H17 cells are critically involved in the pathogenesis of autoimmune diseases such as multiple sclerosis (MS). In this article, we demonstrate that signals delivered by the coinhibitory molecule B7-homologue 1 (B7-H1) via a B7-homologue 1 mouse-IgG2aFc (B7-H1-Ig) fusion protein nearly abolish T H17, but not T H1 and T H2, differentiation via direct interaction with the T cell. These effects were equally pronounced in the absence of programmed death-1 or B7.1 and B7.2 on the T cell side, thus providing clear evidence that B7-H1 modulates T cell differentiation via a novel receptor. Mechanistically, B7-H1 interfered with early TCR-mediated signaling and cytokine-mediated induction of the T H17-determining transcription factors retinoic acid-related orphan receptor g t and IFN regulator factor-4 in a programmed death-1 and B7-independent fashion. In an animal model of MS, active myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalomyelitis, B7-H1-Ig exhibited a significant and long-lasting effect on disease severity upon administration during the first 5 d of the priming phase, which was accompanied by reduced T H17 responses in the periphery and within the CNS. Importantly, B7-H1-Ig was even capable of interfering with T cell encephalitogenicity when interaction with the T cells occurred after priming using an adoptive transfer experimental autoimmune encephalomyelitis model. In line with this, both naive human CD4 + T cells and differentiated T H17 effector cells from MS patients were highly sensitive toward B7-H1-Ig-mediated T H17 suppression. Together, we propose the existence of a novel B7-H1-mediated immune-regulatory pathway in T cells, which selectively limits murine and human T H17 cell responses and might be therapeutically exploited to control T H17-mediated autoimmunity.

KW - Chemistry

UR - http://www.scopus.com/inward/record.url?scp=84943545956&partnerID=8YFLogxK

U2 - 10.4049/jimmunol.1402746

DO - 10.4049/jimmunol.1402746

M3 - Journal articles

C2 - 26378076

VL - 195

SP - 3584

EP - 3595

JO - Journal of immunology (Baltimore, Md. : 1950)

JF - Journal of immunology (Baltimore, Md. : 1950)

SN - 0022-1767

IS - 8

ER -