The helminth TGF-β mimic TGM4 is a modular ligand that binds CD44, CD49d and TGF-β receptors to preferentially target myeloid cells.
The helminth TGF-β mimic TGM4 is a modular ligand that binds CD44, CD49d and TGF-β receptors to preferentially target myeloid cells.
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蠕虫 TGF-β 模拟 TGM4 是一种模块化配体，可结合 CD44、CD49d 和 TGF-β 受体优先靶向骨髓细胞。
DOI：
10.1101/2023.11.13.566701
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发表时间：
2023
期刊：
影响因子：
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通讯作者：
Inman
中科院分区：
文献类型：
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作者：
Singh,ShashiP;Smyth,DanielleJ;Cunningham,Kyle;Mukundan,Ananya;Byeon,Chang-Hyeock;Hinck,CynthiaS;White,MadeleinePJ;Ciancia,Claire;Wosowska,Nątalia;Sanders,Anna;Jin,Regina;Lilla,Sergio;Zanivan,Sara;Schoenherr,Christina;Inman
小鼠寄生虫多回螺旋体表达一组复制免疫调节细胞因子转化生长因子β功能的模块化蛋白，被命名为TGM(转化生长因子βΜIMIC)。多个结构域通过结构域1-3与不同的受体结合，包括转化生长因子-β受体T-βRI(ALK5)和T-βRII，原型家族成员TGM1通过结构域4-5与细胞表面共受体CD44结合。这使得TGM1能够诱导T淋巴细胞Foxp3的表达，这是调节性(Treg)细胞的特征，并激活一系列转化生长因子-β反应的细胞类型。相反，一种相关的蛋白质，TGM4，主要作用于髓系细胞，对T细胞的影响较小，对其他转化生长因子-β反应细胞类型缺乏活性。通过流式细胞仪检测，TGM4能与髓系细胞发生强烈结合，在细胞结合方面优于TGM1。受体结合分析表明，与TGM1相比，TGM4对转化生长因子βR-I(TβRI)的亲和力是TGM1的10倍，而对TβRII的亲和力是TGM1的100倍。因此，TGM4更依赖于共受体结合；除了CD44，TGM4还通过CD44与CD49d(ItGa4)结合，以及通过CD206和Neuropilin-1通过结构域4和5结合。TGM4被发现能有效地调节巨噬细胞群，抑制内毒素驱动的炎性细胞因子的产生，并增强IL-4刺激的反应，如体外和体内的精氨酸酶-1。这些结果表明，TGMs的模块化性质允许微调TβR-和共受体结合域的结合亲和力，以哺乳动物细胞因子无法达到的方式为转化生长因子-β信号建立细胞特异性。
The murine helminth parasite Heligmosomoides polygyrus expresses a family of modular proteins which, replicating the functional activity of the immunomodulatory cytokine TGF-β, have been named TGM (TGF-β Μimic). Multiple domains bind to different receptors, including TGF-β receptors TβRI (ALK5) and TβRII through domains 1–3, and prototypic family member TGM1 binds the cell surface co-receptor CD44 through domains 4–5. This allows TGM1 to induce T lymphocyte Foxp3 expression, characteristic of regulatory (Treg) cells, and to activate a range of TGF-β-responsive cell types. In contrast, a related protein, TGM4, targets a much more restricted cell repertoire, primarily acting on myeloid cells, with less potent effects on T cells and lacking activity on other TGF-β-responsive cell types. TGM4 binds avidly to myeloid cells by flow cytometry, and can outcompete TGM1 for cell binding. Analysis of receptor binding in comparison to TGM1 reveals a 10-fold higher affinity than TGM1 for TGFβR-I (TβRI), but a 100-fold lower affinity for TβRII through Domain 3. Consequently, TGM4 is more dependent on co-receptor binding; in addition to CD44, TGM4 also engages CD49d (Itga4) through Domains 1–3, as well as CD206 and Neuropilin-1 through Domains 4 and 5. TGM4 was found to effectively modulate macrophage populations, inhibiting lipopolysaccharide-driven inflammatory cytokine production and boosting interleukin (IL)-4-stimulated responses such as Arginase-1 in vitro and in vivo. These results reveal that the modular nature of TGMs has allowed the fine tuning of the binding affinities of the TβR- and co-receptor binding domains to establish cell specificity for TGF-β signalling in a manner that cannot be attained by the mammalian cytokine.