Department of Anatomy and Physiology, Kansas State University, Manhattan, KS 66506, USA.
Molecular Graphics and Computation Facility, College of Chemistry, University of California, Berkeley, CA 94720, USA.
Int J Mol Sci. 2021 Mar 18;22(6):3124. doi: 10.3390/ijms22063124.
Beta glucans are known to have immunomodulatory effects that mediated by a variety of mechanisms. In this article, we describe experiments and simulations suggesting that beta-1,3 glucans may promote activation of T cells by a previously unknown mechanism. First, we find that treatment of a T lymphoblast cell line with beta-1,3 oligoglucan significantly increases mRNA levels of T cell activation-associated cytokines, especially in the presence of the agonistic anti-CD3 antibody. This immunostimulatory activity was observed in the absence of dectin-1, a known receptor for beta-1,3 glucans. To clarify the molecular mechanism underlying this activity, we performed a series of molecular dynamics simulations and free-energy calculations to explore the interaction of beta-1,3 oligoglucans with potential immune receptors. While the simulations reveal little association between beta-1,3 oligoglucan and the immune receptor CD3, we find that beta-1,3 oligoglucans bind to CD28 near the region identified as the binding site for its natural ligands CD80 and CD86. Using a rigorous absolute binding free-energy technique, we calculate a dissociation constant in the low millimolar range for binding of 8-mer beta-1,3 oligoglucan to this site on CD28. The simulations show this binding to be specific, as no such association is computed for alpha-1,4 oligoglucan. This study suggests that beta-1,3 glucans bind to CD28 and may stimulate T cell activation collaboratively with T cell receptor activation, thereby stimulating immune function.
β-葡聚糖具有免疫调节作用，其作用机制多种多样。本文描述了一些实验和模拟结果，表明β-1,3 葡聚糖可能通过一种未知的机制促进 T 细胞的激活。首先，我们发现用β-1,3 寡葡聚糖处理 T 淋巴母细胞系可显著增加 T 细胞激活相关细胞因子的 mRNA 水平，尤其是在存在激动性抗 CD3 抗体的情况下。这种免疫刺激活性在缺乏 dectin-1 的情况下也能观察到，dectin-1 是 β-1,3 葡聚糖的已知受体。为了阐明这种活性的分子机制，我们进行了一系列分子动力学模拟和自由能计算，以探索β-1,3 寡葡聚糖与潜在免疫受体的相互作用。虽然模拟结果显示β-1,3 寡葡聚糖与免疫受体 CD3 之间的关联很小，但我们发现β-1,3 寡葡聚糖与 CD28 结合，其位置在被鉴定为天然配体 CD80 和 CD86 结合位点附近。我们使用严格的绝对结合自由能技术，计算出 8 聚体β-1,3 寡葡聚糖与 CD28 上该结合位点的解离常数在低毫摩尔范围内。模拟结果表明这种结合是特异性的，因为对于α-1,4 寡葡聚糖没有计算出这种关联。这项研究表明，β-1,3 葡聚糖与 CD28 结合，并可能与 T 细胞受体激活协同刺激 T 细胞激活，从而刺激免疫功能。
