CD28 co-stimulation in T-cell homeostasis: a recent perspective.
CD28 co-stimulation in T-cell homeostasis: a recent perspective.
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CD28在T细胞稳态中共同刺激：最近的观点。
DOI：
10.2147/itt.s61647
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发表时间：
2015
影响因子：
7.2
通讯作者：
Hünig T
中科院分区：
文献类型：
--
作者：
Beyersdorf N;Kerkau T;Hünig T
T细胞在适应性免疫系统中发挥关键作用，介导细胞免疫并协调整个免疫应答。它们的活化不仅需要T细胞受体识别抗原/主要组织相容性复合物，而且还需要通过与CD 80、CD 86或最近发现的由抗原呈递细胞表达的诱导型共刺激配体结合经由CD 28分子的共刺激。除了通过T细胞受体复合物严格控制共刺激信号外，需要表达与CD 28共享其配体的抑制性受体细胞毒性T淋巴细胞抗原-4（CTLA-4）以避免不适当或延长的T细胞活化。CD 4 + Foxp 3+调节性T（Treg）细胞是自身免疫的重要抑制剂，增加了另一个水平的复杂性，因为它们与传统的非调节性CD 4 + T细胞不同，其产生和稳态强烈依赖于CD 28信号传导。此外，CTLA-4由Treg细胞组成型表达，其中其充当抑制的关键介体，而常规CD 4 + T细胞仅在活化后表达CTLA-4。在这里，我们讨论了最近的见解的分子事件CD 28介导的共刺激，其对基因调控的影响，以及CD 28表达的Treg细胞与传统的CD 4+和CD 8 + T细胞的差异作用。此外，我们总结了令人兴奋的治疗方案，这些方案是从我们目前对T细胞共刺激的理解中产生的。其中一些已经被转化为临床，而另一些由于有希望的临床前结果预计将很快跟进。特别是，我们讨论了2006年失败的CD 28超激动剂TGN 1412的试验，以及这种有效的T细胞激活剂的临床开发的回报。
T-cells play a key role within the adaptive immune system mediating cellular immunity and orchestrating the immune response as a whole. Their activation requires not only recognition of antigen/major histocompatibility complexes by the T-cell receptor but in addition co-stimulation via the CD28 molecule through binding to CD80, CD86, or as recently discovered, inducible co-stimulator ligand expressed by antigen-presenting cells. Apart from tight control of the co-stimulatory signal by the T-cell receptor complex, expression of the inhibitory receptor cytotoxic T-lymphocyte antigen-4 (CTLA-4) sharing its ligands with CD28 is required to avoid inappropriate or prolonged T-cell activation. CD4+ Foxp3+ regulatory T (Treg) cells, which are crucial inhibitors of autoimmunity, add another level of complexity in that they differ from conventional non-regulatory CD4+ T-cells by strongly depending on CD28 signaling for their generation and homeostasis. Moreover, CTLA-4 is constitutively expressed by Treg cells where it serves as a key mediator of suppression, while conventional CD4+ T-cells express CTLA-4 only after activation. Here, we discuss recent insights into the molecular events underlying CD28-mediated co-stimulation, its impact on gene regulation, and the differential role of CD28 expression on Treg cells versus conventional CD4+ and CD8+ T-cells. Moreover, we summarize the exciting therapeutic options which have arisen from our current understanding of T-cell co-stimulation. Some of these have already been translated into the clinic, while others are expected to follow soon due to promising preclinical results. In particular, we discuss the failed 2006 trial of the CD28 superagonist TGN1412, and the return of this potent T-cell activator to clinical development.