Rhodes J, Chen H, Hall S R, Beesley J E, Jenkins D C, Collins P, Zheng B
Molecular Immunology Group, Wellcome Research Laboratories, Beckenham, Kent, UK.
Nature. 1995 Sep 7;377(6544):71-5. doi: 10.1038/377071a0.
Immune responses are orchestrated by CD4 T lymphocytes, which receive a cognitive signal when clonally distributed receptors are occupied by major histocompatibility complex (MHC) class II-bound peptides on antigen-presenting cells (APCs). The APCs provide costimulatory signals, through macromolecules such as CD80, that regulate outcomes in terms of T-cell activation or anergy. We have studied essential complementary chemical events in the form of Schiff base formation between carbonyls and amines that are constitutively expressed on presenting cell and T-cell surfaces and provide a new target for manipulation of immune responses. Here we show that small Schiff base-forming molecules can substitute for the physiological donor of carbonyl groups and provide a costimulatory signal to CD4 Th-cells through a mechanism that activates clofilium-sensitive K+ and Na+ transport. One such molecule, tucaresol, enhances CD4 Th-cell responses, selectively favouring a Th1-type profile of cytokine production. In vivo tucaresol potently enhances CD4 Th-cell priming and CD8 cytotoxic T-cell priming to viral antigens, and has substantial therapeutic activity in murine models of disease.
免疫反应由CD4 T淋巴细胞精心调控，当克隆分布的受体被抗原呈递细胞（APC）上与主要组织相容性复合体（MHC）II类结合的肽占据时，CD4 T淋巴细胞会接收到一个识别信号。APC通过诸如CD80等大分子提供共刺激信号，这些信号从T细胞活化或无反应性方面调节结果。我们研究了在呈递细胞和T细胞表面组成性表达的羰基与胺之间形成席夫碱形式的重要互补化学事件，这为操纵免疫反应提供了一个新靶点。在此我们表明，形成席夫碱的小分子可以替代羰基的生理供体，并通过激活对氯非铵敏感的K+和Na+转运的机制向CD4 Th细胞提供共刺激信号。一种这样的分子，图卡雷索，增强CD4 Th细胞反应，选择性地促进细胞因子产生的Th1型谱。在体内，图卡雷索有力地增强CD4 Th细胞启动和CD8细胞毒性T细胞对病毒抗原的启动，并在疾病的小鼠模型中具有显著的治疗活性。
