CD45 的可溶性胞质尾部通过 TLR4 信号传导调节 T 细胞活化,European Journal of Immunology

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CD45 的可溶性胞质尾部通过 TLR4 信号传导调节 T 细胞活化
European Journal of Immunology ( IF 4.5 ) Pub Date : 2021-10-09 , DOI: 10.1002/eji.202149227
Alexander Puck ₁ , Sarojinidevi Künig ₁ , Madhura Modak ₁ , Lara May ₁ , Pia Fritz ₁ , Claire Battin ₁ , Katharina Radakovics ₁ , Peter Steinberger ₁ , Birgit M Reipert ₂ , Brian A Crowe ₂ , Johannes Stöckl ₁

Affiliation

CD45 的可溶性胞质尾 (ct-CD45) 是 CD45 的切割片段，在人类吞噬细胞的激活过程中产生。在释放到细胞外空间后，ct-CD45 与人类 T 细胞结合并在体外抑制它们的活化。在这里，我们研究了 TLR4 作为 ct-CD45 受体的潜在作用。用 ct-CD45 处理 Jurkat TLR4/CD14 报告细胞诱导报告基因 NFκB-eGFP 的上调，并且可以被 TLR4 信号传导抑制剂阻断。相反，ct-CD45 不促进表达 TLR1、TLR2 和 TLR6 转基因的报告细胞中 NFκB 控制的 eGFP 诱导，并且不会导致 Jurkat 报告细胞系中转录因子 NFκB、AP-1 和 NFAT 的激活表达内源性 TLR5。而且，在体外试验中，ct-CD45 与重组 TLR4 结合，并且在氧化的 1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphorylcholine 存在下这种关联降低。用 mAb HTA125 阻断 TLR4 部分逆转了 ct-CD45 介导的 T 细胞增殖抑制。有趣的是，用 mAb W7C11 靶向 TLR4 也抑制了 T 细胞增殖。总之，本研究的结果表明，ct-CD45 通过 T 细胞上的非经典 TLR4 激活途径发挥作用，从而调节 TCR 信号传导。

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The soluble cytoplasmic tail of CD45 regulates T-cell activation via TLR4 signaling

The soluble cytoplasmic tail of CD45 (ct-CD45) is a cleavage fragment of CD45, that is generated during the activation of human phagocytes. Upon release to the extracellular space, ct-CD45 binds to human T cells and inhibits their activation in vitro. Here, we studied the potential role of TLR4 as a receptor for ct-CD45. Treatment of Jurkat TLR4/CD14 reporter cells with ct-CD45 induced the upregulation of the reporter gene NFκB-eGFP and could be blocked by inhibitors of TLR4 signaling. Conversely, ct-CD45 did not promote the NFκB-controlled eGFP induction in reporter cells expressing TLR1, TLR2, and TLR6 transgenes and did not lead to the activation of the transcription factors NFκB, AP-1, and NFAT in a Jurkat reporter cell line expressing endogenous TLR5. Moreover, ct-CD45 binds to recombinant TLR4 in an in vitro assay and this association was reduced in the presence of oxidized 1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphorylcholine. Blockade of TLR4 with mAb HTA125 partially reversed the ct-CD45-mediated inhibition of T-cell proliferation. Interestingly, targeting of TLR4 with mAb W7C11 also suppressed T-cell proliferation. In summary, the results of this study demonstrate that ct-CD45 acts via a noncanonical TLR4 activation pathway on T cells, which modulates TCR signaling.

更新日期：2021-12-15

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