TLR-MyD88 signaling blockades inhibit refractory B-1b cell immune responses to transplant-related glycan antigens
TLR-MyD88 signaling blockades inhibit refractory B-1b cell immune responses to transplant-related glycan antigens
复制标题
TLR-MyD88 信号传导阻断抑制难治性 B-1b 细胞对移植相关聚糖抗原的免疫反应
DOI：
10.1111/ajt.16288
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发表时间：
2021
期刊：
影响因子：
--
通讯作者：
Ohdan H.
中科院分区：
文献类型：
--
作者：
Sakai H;Tanaka Y;Tanaka A;Ohdan H.
对T细胞非依赖性（TI）碳水化合物抗原（Ag）的难治性B细胞应答是对ABO不相容的同种异体移植物和来自其他物种的异种移植物的排斥反应的关键驱动因素。为了探讨Toll样受体（TLR）和B细胞受体（BCR）之间相互作用在TI B细胞免疫中的生物学意义，我们在此使用MyD 88、TRIF和α-半乳糖基转移酶缺陷小鼠研究TI移植相关聚糖-Ag暴露期间B细胞表型和功能特性。单独BCR刺激诱导分化为CD 5 high（B-1a）细胞，其对钙调磷酸酶抑制剂（CNI）高度敏感，而TLR和BCR的共刺激以MyD 88依赖性和CNI抗性方式诱导分化为CD 5 dim（B-1 B）细胞。B-1 B细胞中MyD 88依赖性TLR刺激增强了BCR-钙调神经磷酸酶途径中的下游因子，包括活化T细胞的核因子，胞质1（NFATc 1）。TLR抑制剂与CNI一起消除了针对ABO血型Ag的难治性B-1 B b细胞免疫应答，而通过使用布鲁顿酪氨酸激酶抑制剂和组蛋白脱乙酰酶抑制剂阻断BCR和TLRs-MyD 88消除了针对Gal聚糖Ag的难治性B-1 B b细胞免疫应答。因此，本研究为通过阻断BCR和TLRs-MyD 88信号来克服难治性移植相关抗聚糖Ab产生的新型治疗方法提供了理论基础。
Refractory B cell responses to T cell-independent (TI) carbohydrate antigens (Ags) are critical drivers of rejection reactions to ABO-incompatible allogeneic grafts and xenogeneic grafts from other species. To explore the biological significance of crosstalk between Toll-like receptors (TLRs) and B cell receptors (BCRs) in the TI B cell immunity, we here used MyD88-, TRIF-, and α-galactosyltransferase-deficient mice to study B cell phenotypes and functional properties during TI transplant-related glycan-Ag exposure. BCR stimulation alone induced differentiation into CD5high (B-1a) cells, which were highly sensitive to a calcineurin inhibitor (CNI), while co-stimulation of TLRs and BCRs induced differentiation into CD5dim (B-1b) cells in MyD88-dependent and CNI-resistant manners. MyD88-dependent TLR stimulation in B-1b cells enhanced downstream factors in the BCR–calcineurin pathway, including a nuclear factor of activated T-cells, cytoplasmic 1 (NFATc1). TLR inhibitor together with CNI abrogated refractory B-1b cell immune responses against the ABO-blood group Ags, while blocking both BCRs and TLRs–MyD88 by using Bruton’s tyrosine kinase inhibitor and histone deacetylase inhibitor abrogated refractory B-1b cell immune responses against Gal-glycan Ags. Thus, this study provides a rationale for a novel therapeutic approach to overcome refractory transplant-related anti-glycan Ab production by blocking both BCR and TLRs–MyD88 signals.