TY - JOUR
T1 - Immunoinhibitory checkpoint deficiency in medium & large vessel vasculitis
AU - Zhang, Hui
AU - Watanabe, Ryu
AU - Berry, Gerald J.
AU - Vaglio, Augusto
AU - Liao, Yaping Joyce
AU - Warrington, Kenneth J.
AU - Goronzy, Jörg J.
AU - Weyand, Cornelia M.
N1 - Funding Information:
This work was supported by the National Institutes of Health Grants R01 AR042527, R01 HL117913, R01 Al 108906, and P01 HL129941 (to C.M.W.), and R01 AI108891, R01 AG045779. U19 AI057229, U19 AI057266, and I01 BX001669 (toJJ.G.). R.W. received fellowship support from the Govenar Discovery Fund. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
PY - 2017/2/7
Y1 - 2017/2/7
N2 - Giant cell arteritis (GCA) causes autoimmune inflammation of the aorta and its large branches, resulting in aortic arch syndrome, blindness, and stroke. CD4+ T cells and macrophages form organized granulomatous lesions in the walls of affected arteries, destroy the tunica media, and induce ischemic organ damage through rapid intimal hyperplasia and luminal occlusion. Pathogenic mechanisms remain insufficiently understood; specifically, it is unknown whether the unopposed activation of the immune system is because of deficiency of immunoinhibitory checkpoints. Transcriptome analysis of GCA-Affected temporal arteries revealed low expression of the coinhibitory ligand programmed death ligand-1 (PD-L1) concurrent with enrichment of the programmed death-1 (PD-1) receptor. Tissue-residing and ex vivo-generated dendritic cells (DC) from GCA patients were PD-L1lo, whereas the majority of vasculitic T cells expressed PD-1, suggesting inefficiency of the immunoprotective PD-1/PD-L1 immune checkpoint. DC-PD-L1 expression correlated inversely with clinical disease activity. In human artery-SCID chimeras, PD-1 blockade exacerbated vascular inflammation, enriched for PD- 1+ effector T cells, and amplified tissue production of multiple T-cell effector cytokines, including IFN-γ, IL-17, and IL-21. Arteries infiltrated by PD-1+ effector T cells developed microvascular neoangiogenesis as well as hyperplasia of the intimal layer, implicating T cells in the maladaptive behavior of vessel wall endogenous cells. Thus, in GCA, a breakdown of the tissue-protective PD1/PD-L1 checkpoint unleashes vasculitic immunity and regulates the pathogenic remodeling of the inflamed arterial wall.
AB - Giant cell arteritis (GCA) causes autoimmune inflammation of the aorta and its large branches, resulting in aortic arch syndrome, blindness, and stroke. CD4+ T cells and macrophages form organized granulomatous lesions in the walls of affected arteries, destroy the tunica media, and induce ischemic organ damage through rapid intimal hyperplasia and luminal occlusion. Pathogenic mechanisms remain insufficiently understood; specifically, it is unknown whether the unopposed activation of the immune system is because of deficiency of immunoinhibitory checkpoints. Transcriptome analysis of GCA-Affected temporal arteries revealed low expression of the coinhibitory ligand programmed death ligand-1 (PD-L1) concurrent with enrichment of the programmed death-1 (PD-1) receptor. Tissue-residing and ex vivo-generated dendritic cells (DC) from GCA patients were PD-L1lo, whereas the majority of vasculitic T cells expressed PD-1, suggesting inefficiency of the immunoprotective PD-1/PD-L1 immune checkpoint. DC-PD-L1 expression correlated inversely with clinical disease activity. In human artery-SCID chimeras, PD-1 blockade exacerbated vascular inflammation, enriched for PD- 1+ effector T cells, and amplified tissue production of multiple T-cell effector cytokines, including IFN-γ, IL-17, and IL-21. Arteries infiltrated by PD-1+ effector T cells developed microvascular neoangiogenesis as well as hyperplasia of the intimal layer, implicating T cells in the maladaptive behavior of vessel wall endogenous cells. Thus, in GCA, a breakdown of the tissue-protective PD1/PD-L1 checkpoint unleashes vasculitic immunity and regulates the pathogenic remodeling of the inflamed arterial wall.
KW - Autoimmunity
KW - Immune checkpoint
KW - PD-1
KW - T cells
KW - Vasculitis
UR - http://www.scopus.com/inward/record.url?scp=85011650396&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85011650396&partnerID=8YFLogxK
U2 - 10.1073/pnas.1616848114
DO - 10.1073/pnas.1616848114
M3 - Article
C2 - 28115719
AN - SCOPUS:85011650396
SN - 0027-8424
VL - 114
SP - E970-E979
JO - Proceedings of the National Academy of Sciences of the United States of America
JF - Proceedings of the National Academy of Sciences of the United States of America
IS - 6
ER -