Department of Pathology, Sapporo Medical University School of Medicine, Sapporo 060-8556, Japan.
Immunotherapy. 2012 Aug;4(8):841-52. doi: 10.2217/imt.12.75.
There has been growing evidence that heat-shock protein (HSP) functions as an endogenous immunomodulator for innate and adaptive immune responses. Since HSPs inherently act as chaperones within cells, passive release (e.g., by cell necrosis) and active release (including release by secretion in the form of an exosome) have been suggested as mechanisms of HSP release into the extracellular milieu. Such extracellular HSPs have been shown to be activators of innate immune responses through Toll-like receptors. However, it has also been suggested that HSPs augment the ability of associated innate ligands such as lipopolysaccharides to stimulate cytokine production and dendritic cell maturation. More interestingly, a recent study has demonstrated that innate immune responses elicited by danger signals were regulated spatiotemporally and that can be manipulated by HSPs, thereby controlling immune responses. We will discuss how spatiotemporal regulation of HSP-chaperoned molecules within antigen-presenting cells affects adaptive immunity via antigen cross-presentation and innate immune responses. Precise analysis of HSP biology should lead to the establishment of effective HSP-based immunotherapy.
越来越多的证据表明热休克蛋白 (HSP) 作为先天和适应性免疫反应的内源性免疫调节剂发挥作用。由于 HSP 在细胞内固有地充当伴侣蛋白，因此已经提出了被动释放（例如，通过细胞坏死）和主动释放（包括以细胞外体形式分泌的释放）作为 HSP 释放到细胞外环境的机制。已经表明这种细胞外 HSP 通过 Toll 样受体激活先天免疫反应。然而，也有人提出 HSP 增强了相关先天配体（如脂多糖）刺激细胞因子产生和树突状细胞成熟的能力。更有趣的是，最近的一项研究表明，危险信号引发的先天免疫反应在时空上受到调节，并且可以通过 HSP 进行操纵，从而控制免疫反应。我们将讨论抗原呈递细胞内 HSP 伴侣分子的时空调节如何通过抗原交叉呈递和先天免疫反应影响适应性免疫。对 HSP 生物学的精确分析应该会导致建立有效的基于 HSP 的免疫疗法。
