Basic Research Program, Scientific Application and International Corporation–Frederick, Inc, Frederick, Frederick, MD 21702, USA.
J Exp Med. 2012 Jan 16;209(1):157-71. doi: 10.1084/jem.20101354. Epub 2011 Dec 19.
Alarmins are endogenous mediators capable of promoting the recruitment and activation of antigen-presenting cells (APCs), including dendritic cells (DCs), that can potentially alert host defense against danger signals. However, the relevance of alarmins to the induction of adaptive immune responses remains to be demonstrated. In this study, we report the identification of HMGN1 (high-mobility group nucleosome-binding protein 1) as a novel alarmin and demonstrate that it contributes to the induction of antigen-specific immune responses. HMGN1 induced DC maturation via TLR4 (Toll-like receptor 4), recruitment of APCs at sites of injection, and activation of NF-κB and multiple mitogen-activated protein kinases in DCs. HMGN1 promoted antigen-specific immune response upon co-administration with antigens, and Hmgn1(-/-) mice developed greatly reduced antigen-specific antibody and T cell responses when immunized with antigens in the presence of lipopolysaccharide (LPS). The impaired ability of Hmgn1(-/-) mice to mount antigen-specific immune responses was accompanied by both deficient DC recruitment at sites of immunization and reduced production of inflammatory cytokines. Bone marrow chimera experiments revealed that HMGN1 derived from nonleukocytes was critical for the induction of antigen-specific antibody and T cell responses. Thus, extracellular HMGN1 acts as a novel alarmin critical for LPS-induced development of innate and adaptive immune responses.
警报素是内源性介质，能够促进抗原呈递细胞（APCs），包括树突状细胞（DCs）的募集和激活，从而有可能提醒宿主防御危险信号。然而，警报素与适应性免疫反应的诱导之间的相关性仍有待证明。在这项研究中，我们鉴定了 HMGN1（高迁移率族核小体结合蛋白 1）作为一种新型警报素，并证明它有助于诱导抗原特异性免疫反应。HMGN1 通过 TLR4（Toll 样受体 4）诱导 DC 成熟，在注射部位募集 APC，并在 DC 中激活 NF-κB 和多种丝裂原活化蛋白激酶。HMGN1 与抗原共同给药时可促进抗原特异性免疫反应，而在 LPS 存在下用抗原免疫时，Hmgn1(-/-)小鼠产生的抗原特异性抗体和 T 细胞反应大大减少。Hmgn1(-/-)小鼠产生抗原特异性免疫反应的能力受损，同时伴随着免疫部位 DC 募集缺陷和炎症细胞因子产生减少。骨髓嵌合体实验表明，来自非白细胞的 HMGN1 对于诱导抗原特异性抗体和 T 细胞反应至关重要。因此，细胞外 HMGN1 是 LPS 诱导先天和适应性免疫反应发展所必需的新型警报素。
