New York University School of Medicine, New York, NY, USA.
New York University School of Medicine, New York, NY, USA.
J Autoimmun. 2018 Aug;92:57-66. doi: 10.1016/j.jaut.2018.05.005. Epub 2018 Jun 13.
Apoptotic cell receptors contribute to the induction of tolerance by modulating dendritic cell function following the uptake of apoptotic cells or microparticles. Dendritic cells that have bound or ingested apoptotic cells produce only low amounts of pro-inflammatory cytokines and fail to prime effector T cell responses. Specifically, ligation of the apoptotic cell receptor CR3 (CD11 b/CD18) on human monocyte-derived dendritic cells (moDC) down-modates proinflammatory cytokine secretion, but the consequences for human Th17 cell homeostasis and effector responses remain unknown. Here, we aimed to establish whether CD11b-ligated moDC modulate Th17 cell effector reponses to assess their potential for future use in moDC-based suppressive immunotherapy.
We generated a bead-based surrogate system to target CD11b on monocyte-derived human dendritic cells and examined the effects of CD11b ligation on Th17-skewing cytokine secretion, priming, expansion and functional plasticity in DC/T cell co-culture systems at the poly- and monoclonal level.
We show that Th17 cell expansion within the human memory CD4 T cell compartment was efficiently constricted by targeting the CD11b receptor on moDC. This tolerogenic capacity was primarily dependent on cytokine skewing. Furthermore, ligation of CD11b on healthy homozygous carriers of the rs11143679 (ITGAM) variant - a strong genetic susceptibility marker for human systemic lupus erythematosus - also down-modulated the secretion of Th17-skewing cytokines.
Overall, our findings underline the potential of targeted CD11b ligation on human dendritic cells for the engineering of suppressive immunotherapy for Th17-related autoimmune disorders.
凋亡细胞受体通过调节树突状细胞功能，在摄取凋亡细胞或微粒后诱导耐受。结合或吞噬凋亡细胞的树突状细胞仅产生少量促炎细胞因子，并且不能启动效应 T 细胞反应。具体而言，在人单核细胞衍生的树突状细胞（moDC）上，凋亡细胞受体 CR3（CD11b/CD18）的交联下调了促炎细胞因子的分泌，但是对人 Th17 细胞稳态和效应器反应的后果仍不清楚。在这里，我们旨在确定是否 CD11b 交联的 moDC 调节 Th17 细胞效应反应，以评估其在基于 moDC 的抑制性免疫治疗中的潜在用途。
我们生成了一种基于珠子的替代系统来靶向单核细胞衍生的人类树突状细胞上的 CD11b，并在单核细胞衍生的人类树突状细胞和 DC/T 细胞共培养系统中，在多克隆和单克隆水平上，检查了 CD11b 交联对 Th17 细胞偏向细胞因子分泌、启动、扩增和功能可塑性的影响。
我们表明，通过靶向 moDC 上的 CD11b，有效地限制了人类记忆 CD4 T 细胞区室中 Th17 细胞的扩增。这种耐受性主要依赖于细胞因子的偏向性。此外，在健康的 rs11143679（ITGAM）变体纯合子携带者（一种人类系统性红斑狼疮的强遗传易感性标志物）上，CD11b 的交联也下调了 Th17 偏向性细胞因子的分泌。
总体而言，我们的研究结果强调了靶向人类树突状细胞上的 CD11b 进行 Th17 相关自身免疫性疾病抑制性免疫治疗的潜力。
