The University of Queensland Diamantina Institute, The University of Queensland, Woolloongabba, Queensland, Australia.
Centre for Inflammatory Diseases, Monash University Department of Medicine, Monash Medical Centre, Clayton, Victoria, Australia.
JCI Insight. 2019 Sep 19;4(18):126025. doi: 10.1172/jci.insight.126025.
Autoimmune diseases resulting from MHC class II-restricted autoantigen-specific T cell immunity include the systemic inflammatory autoimmune conditions rheumatoid arthritis and vasculitis. While currently treated with broad-acting immunosuppressive drugs, a preferable strategy is to regulate antigen-specific effector T cells (Teffs) to restore tolerance by exploiting DC antigen presentation. We targeted draining lymph node (dLN) phagocytic DCs using liposomes encapsulating 1α,25-dihydroxyvitamin D3 (calcitriol) and antigenic peptide to elucidate mechanisms of tolerance used by DCs and responding T cells under resting and immunized conditions. PD-L1 expression was upregulated in dLNs of immunized relative to naive mice. Subcutaneous administration of liposomes encapsulating OVA323-339 and calcitriol targeted dLN PD-L1hi DCs of immunized mice and reduced their MHC class II expression. OVA323-339/calcitriol liposomes suppressed expansion, differentiation, and function of Teffs and induced Foxp3+ and IL-10+ peripheral Tregs in an antigen-specific manner, which was dependent on PD-L1. Peptide/calcitriol liposomes modulated CD40 expression by human DCs and promoted Treg induction in vitro. Liposomes encapsulating calcitriol and disease-associated peptides suppressed the severity of rheumatoid arthritis and Goodpasture's vasculitis models with suppression of antigen-specific memory T cell differentiation and function. Accordingly, peptide/calcitriol liposomes leverage DC PD-L1 for antigen-specific T cell regulation and induce antigen-specific tolerance in inflammatory autoimmune diseases.
自身免疫性疾病是由 MHC Ⅱ类限制性自身抗原特异性 T 细胞免疫引起的，包括全身性炎症性自身免疫性疾病类风湿关节炎和血管炎。虽然目前采用广泛作用的免疫抑制剂治疗，但更好的策略是通过利用树突状细胞（DC）抗原呈递来调节抗原特异性效应 T 细胞（Teffs）以恢复耐受性。我们使用包封 1α,25-二羟维生素 D3（钙三醇）和抗原肽的脂质体靶向引流淋巴结（dLN）吞噬 DC，以阐明 DC 和在静息和免疫条件下反应性 T 细胞所使用的耐受机制。与未免疫的小鼠相比，免疫小鼠的引流淋巴结中 PD-L1 的表达上调。与未免疫的小鼠相比，皮下给予包封 OVA323-339 和钙三醇的脂质体靶向免疫小鼠的引流淋巴结 PD-L1hi DC，并降低其 MHC Ⅱ类表达。OVA323-339/钙三醇脂质体以抗原特异性方式抑制 Teffs 的扩增、分化和功能，并诱导外周 Foxp3+和 IL-10+Treg，这依赖于 PD-L1。肽/钙三醇脂质体调节人 DC 的 CD40 表达，并在体外促进 Treg 的诱导。包封钙三醇和疾病相关肽的脂质体抑制类风湿关节炎和 Goodpasture 血管炎模型的严重程度，抑制抗原特异性记忆 T 细胞分化和功能。因此，肽/钙三醇脂质体利用 DC PD-L1 进行抗原特异性 T 细胞调节，并在炎症性自身免疫性疾病中诱导抗原特异性耐受。
