Distinct roles of ICOS and CD40L in human T-B cell adhesion and antibody production
Distinct roles of ICOS and CD40L in human T-B cell adhesion and antibody production
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ICOS 和 CD40L 在人 T-B 细胞粘附和抗体产生中的独特作用
DOI：
10.1016/j.cellimm.2021.104420
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发表时间：
2021-08-18
影响因子：
4.3
通讯作者：
Wang, Ying
中科院分区：
文献类型：
--
作者：
Liu, Zhicui;Liu, Shuai;Wang, Ying
在小鼠模型中，CD 40-CD 40 L和诱导型共刺激分子（ICOS）-ICOSL连接在CD 4 + T-B相互作用中对B细胞活化和分化起关键作用。本文通过微管粘附实验和体外CD 4 + T-B细胞共培养系统，探讨了它们在人CD 4 + T-B细胞粘附和IgG/IgM产生中的作用。在体外，TCR/CD 28刺激后，随着CD 4 + T细胞上的CD 40 L和ICOS表达的上调，活化的CD 4 + T细胞与自体B细胞在单细胞水平上相比于静息的对应物表现出增强的粘附。阻断ICOS可显著抑制CD 4 + T细胞和B细胞之间的粘附，而阻断CD 40 L的作用较小。相反，当B细胞与活化的CD 4 + T细胞共培养时，CD 40 L的阻断导致IgG/IgM产生的显著减少，同时CD 19 hi B细胞的诱导减少。然而，ICOS阻断对IgG/IgM产生的衰减较小。CD 40-CD 40 L和ICOS-ICOSL在系统性红斑狼疮患者CD 4 + T-B细胞相互作用中对细胞粘附和IgG/IgM的产生也有不同的作用。CD 40 L而不是ICOS的阻断导致CD 19 hi B细胞和总B细胞中Pyk 2磷酸化的显著降低。因此，我们的研究提供了证据表明，活化的CD 4 + T细胞上的CD 40 L和ICOS无论是在体外活化还是在致病状态下，在CD 4 + T-B细胞相互作用过程中功能受损。虽然ICOS-ICOSL连接更可能参与细胞粘附，但CD 40-CD 40 L为B细胞分化和IgG/IgM产生提供不可或缺的信号。本研究结果提示CD 40-CD 40 L和ICOS-ICOL L对CD 4 + T细胞的共刺激作用是分离的，对B细胞的活化和分化可能有帮助。
CD40-CD40L and inducible co-stimulatory molecule (ICOS)-ICOSL ligations are demonstrated to play critical roles in CD4+ T-B interaction for B cell activation and differentiation in mouse models. Herein, by using a micropipette adhesion assay and an in vitro CD4+ T-B cell coculture system simultaneously, we intended to dissect their roles in human CD4+ T-B adhesion and IgG/IgM production. With the upregulation of CD40L and ICOS expressions on CD4+ T cells upon TCR/CD28 stimulation in vitro, activated CD4+ T cells exhibited enhanced adhesion with autologous B cells at a single cell level when compared to the resting counterparts. Blockade of ICOS dramatically damped the adhesion between CD4+ T and B cells whereas less effect of CD40L blockade was observed. On the contrary, blockade of CD40L led to the dramatic decrease in IgG/IgM production when B cells were cocultured with activated CD4+ T cells together with the decrease in the induction of CD19hi B cells. However, ICOS blockade displayed less attenuation on IgG/IgM production. Distinct roles of CD40-CD40L and ICOS-ICOSL in cell adhesion and IgG/IgM production were also observed in CD4+ T-B cell interaction in system lupus erythematosus patients. The blockade of CD40L, rather than ICOS, led to the dramatic decrease in the phosphorylation of Pyk2 in CD19hi B cells and total B cells. Our study thus provides the evidence that CD40L and ICOS on activated CD4+ T cells either upon in vitro activation or at the pathogenic state function diversely during CD4+ T-B cell interactions. While ICOS-ICOSL ligation is more likely to be engaged in cell adhesion, CD40-CD40L provides indispensable signal for B cell differentiation and IgG/IgM production. Our results are thus indicative for the segregating costimulation of CD40-CD40L and ICOS-ICOSL on CD4+ T cells for B cell activation and differentiation, which might be helpful for the dissection of SLE pathogenesis.