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Immunoinhibitory Checkpoint Deficiency in Medium and Large Vessel Vasculitis

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Immunoinhibitory Checkpoint Deficiency in Medium and Large Vessel Vasculitis Immunoinhibitory checkpoint deficiency in medium and large vessel vasculitis Hui Zhanga,1, Ryu Watanabea,1, Gerald J. Berryb, Augusto Vaglioc, Yaping Joyce Liaod, Kenneth J. Warringtone, Jörg J. Goronzya, and Cornelia M. Weyanda,2 aDepartment of Medicine, Division of Immunology and Rheumatology, Stanford University School of Medicine, Stanford, CA 94305; bDepartment of Pathology, Stanford University School of Medicine, Stanford, CA 94305; cDivision of Nephrology, University Hospital of Parma, 43100 Parma, Italy; dDepartment of Ophthalmology, Stanford Byers Eye Institute, Stanford University School of Medicine, Stanford, CA 94305; and eDivision of Rheumatology, Mayo Clinic College of Medicine, Rochester, MN 55905 Edited by Tasuku Honjo, Graduate School of Medicine, Kyoto University, Kyoto, Japan, and approved December 19, 2016 (received for review October 10, 2016) Giant cell arteritis (GCA) causes autoimmune inflammation of the wall and the immunoprivileged tissue site. Their role in controlling aorta and its large branches, resulting in aortic arch syndrome, the influx of immune cells into the mural structures remains un- + blindness, and stroke. CD4 T cells and macrophages form orga- defined. Similarly, understanding how antigen-nonspecific factors nized granulomatous lesions in the walls of affected arteries, de- affect the intensity and the quality of the vasculitogenic immune stroy the tunica media, and induce ischemic organ damage through response could redefine critical pathogenic processes with a major rapid intimal hyperplasia and luminal occlusion. Pathogenic mecha- impact on immunosuppressive strategies (10). nisms remain insufficiently understood; specifically, it is unknown T-cell–dependent immune responses are fine-tuned by a mul- whether the unopposed activation of the immune system is because titude of costimulatory and coinhibitory signals, provided by re- – of deficiency of immunoinhibitory checkpoints. Transcriptome anal- ceptor ligand interactions that modulate TCR-initiated signaling ysis of GCA-affected temporal arteries revealed low expression of cascades (11). Such immune checkpoints are crucial for the the coinhibitory ligand programmed death ligand-1 (PD-L1) concur- maintenance of self-tolerance, prevent autoimmune disease, and rent with enrichment of the programmed death-1 (PD-1) receptor. protect against collateral tissue damage (12). Conversely, excessive Tissue-residing and ex vivo-generated dendritic cells (DC) from GCA expression of immune checkpoint proteins has been associated patients were PD-L1lo, whereas the majority of vasculitic T cells with immune resistance mechanisms, prominently used by tumor expressed PD-1, suggesting inefficiency of the immunoprotective cells to escape from antitumor immunity (13). Recent successes in PD-1/PD-L1 immune checkpoint. DC–PD-L1 expression correlated in- cancer immunotherapy have highlighted the importance of in- versely with clinical disease activity. In human artery-SCID chimeras, hibitory immune checkpoints that stop antigen-reactive T cells. PD-1 blockade exacerbated vascular inflammation, enriched for PD- Specifically, monoclonal antibodies that block the programmed + 1 effector T cells, and amplified tissue production of multiple T-cell death-1/programmed death ligand-1 (PD-1/PD-L1) pathway have effector cytokines, including IFN-γ, IL-17, and IL-21. Arteries infil- yielded unprecedented therapeutic benefit in patients with ad- + vanced solid tumors (14–16). PD-1 is expressed on activated T and trated by PD-1 effector T cells developed microvascular neoangio- B cells and its engagement by its ligands PD-L1 or PD-L2 disrupts genesis as well as hyperplasia of the intimal layer, implicating T cells kinase activity in the TCR-activation cascade through the phos- in the maladaptive behavior of vessel wall endogenous cells. Thus, phatase SHP2. Resulting immunosuppression involves several in GCA, a breakdown of the tissue-protective PD1/PD-L1 checkpoint mechanisms, including T-cell apoptosis, T-cell exhaustion, T-cell unleashes vasculitic immunity and regulates the pathogenic remod- anergy, T-cell IL-10 production, and Treg induction. eling of the inflamed arterial wall. vasculitis | T cells | immune checkpoint | autoimmunity | PD-1 Significance Antigen recognition by the immune system triggers rapid, iant cell arteritis (GCA) is a granulomatous vasculitis with a specific, and protective responses, which are counterbalanced stringent tissue tropism, named after the multinucleated G by inhibitory checkpoints to minimize potentially harmful im- giant cells that populate the inflammatory lesions in the arterial + munity. The programmed death-1/ programmed death ligand-1 walls. Granulomatous infiltrates composed of CD4 T cells and (PD-1/PD-L1) checkpoint is overreactive in cancer patients, macrophages penetrate from the adventitia into the media and curbing antitumor immunity. Whether a failing PD-1/PD-L1 destroy the lamina elastica interna. T cells with identical T-cell checkpoint contributes to spontaneous autoimmune disease in receptor (TCR) sequences have been isolated from spatially humans is unknown. Here, we found that in patients with the distinct lesions (1, 2), highly suggestive for antigen-driven T-cell autoimmune vasculitis giant cell arteritis, antigen-presenting activation, yet no singular vasculitogenic antigen has been defined. cells provide insufficient negative signaling; unleashing highly Lesional T cells provide a spectrum of effector functions, suspi- activated T cells to infiltrate and damage the walls of large ciously diverse, and ranging from the production of IFN-γ, IL-17, arteries. Thus, immunoinhibitory signals protect large arteries and IL-9 to IL-21 (3, 4). Similarly, multiple functional macrophage against inflammatory attack and checkpoint activation may be subsets participate in granuloma formation, spanning from mac- a suitable strategy to treat autoimmune vasculitis. rophages committed to cytokine production (IL-6, IL-1β), to those releasing reactive oxygen species, to those providing growth fac- – Author contributions: J.J.G. and C.M.W. designed research; H.Z. and R.W. performed re- tors (PDGF, FGF) and angiogenic factors (VEGF) (5 7). search; G.J.B. supervised tissue analysis; H.Z., R.W., G.J.B., A.V., Y.J.L., K.J.W., J.J.G., and The wall layers of large and medium vessels have features of C.M.W. analyzed data; Y.J.L. and K.J.W. recruited patients; and J.J.G. and C.M.W. wrote an immunoprivileged niche (8) and the invasion of inflammatory the paper. cells in GCA essentially breaks this immune privilege. Under The authors declare no conflict of interest. physiologic conditions endogenous dendritic cells (DC), so-called This article is a PNAS Direct Submission. vascular DC (vasDC), populate the arterial wall in a vessel-specific 1H.Z. and R.W. contributed equally to this work. distribution pattern and may protect against immune attack (9). 2To whom correspondence should be addressed. Email: [email protected]. Localized in the adventitial layer, such vasDC are close to the vasa This article contains supporting information online at www.pnas.org/lookup/suppl/doi:10. vasorum, and are positioned between the vascular access to the 1073/pnas.1616848114/-/DCSupplemental. E970–E979 | PNAS | Published online January 23, 2017 www.pnas.org/cgi/doi/10.1073/pnas.1616848114 Downloaded by guest on September 24, 2021 The contrasting scenario to immune resistance is exuberant Table 1. Clinical characteristics of patients with GCA PNAS PLUS immunity, leading to immune-mediated tissue injury and auto- Parameters Patients (n = 68) immune diseases. PD-1 and PD-L1 deficiency have been associ- ated with a lupus-like syndrome (17) and a dilated myocardiopathy Age (mean ± SD) 72.7 ± 8.1 (18), respectively. Lack of PD-L1 or PD-1 exacerbates murine Female 76.5% diabetes and experimental autoimmune encephalitis (19, 20) and Ethnicity PD-L1 overexpression reduces spinal cord T-cell infiltrates (21). − − Caucasian 86.8% PD-L1 / antigen-presenting cells (APCs) fail to convert naïve + −/− Hispanic 8.8% CD4 T cells into Tregs (22), and PD-1 mice are prone to African American 4.4% enrich for Th1 and Th17 cells (23). Headaches 72.1% Guided by a transcriptomic signature of GCA-affected arteries Eye involvement 41.1% that lacked expression of the inhibitory ligand PD-L1, we have explored the role of the PD pathway in regulating the intensity Jaw claudication 23.5% Polymyalgia rheumatica 61.8% and the functional orientation of vasculitogenic T-cell responses. ± ± GCA vascular lesions are occupied by PD-L1lo DCs and PD-1hi Disease duration (mean SD, mo) 15.2 24.0 T cells. PD-L1lo DCs from GCA patients enhance T-cell acti- Disease activity vation and proliferative expansion. In a humanized mouse model High 66.2% of vasculitis, treatment with anti–PD-1 antibodies effectively Moderate 11.8% accelerates the recruitment and retention of T cells and inten- Low 22.1% sifies T-cell and macrophage responses in the inflamed artery. ESR (mean ± SD, mm/h) 44.6 ± 31.1 Vasculitogeneic T cells produce IFN-γ, IL-17, and IL-21, sus- CRP (mean ± SD, mg/dL) 4.2 ± 4.5 taining multifunctional effector functions. Accumulation of such Untreated 35.3% multifunctional T-cell populations is associated with the rapid Prednisone (mg/d, mean ± SD) 13.4 ± 18.9 outgrowth of hyperplastic intima, activation of endothelial cells, and the induction of microvascular neoangiogenesis, connecting T cells to disease-relevant remodeling processes in the vascular Laboratory and chimeras were generated
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