A distinct topology of BTN3A IgV and B30.2 domains controlled by juxtamembrane regions favors optimal human γδ T cell phosphoantigen sensing.
A distinct topology of BTN3A IgV and B30.2 domains controlled by juxtamembrane regions favors optimal human γδ T cell phosphoantigen sensing.
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DOI：
10.1038/s41467-023-41938-8
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发表时间：
2023-11-22
影响因子：
16.6
通讯作者：
Herrmann, Thomas
中科院分区：
文献类型：
--
作者：
Karunakaran, Mohindar M.;Subramanian, Hariharan;Jin, Yiming;Mohammed, Fiyaz;Kimmel, Brigitte;Juraske, Claudia;Starick, Lisa;Noehren, Anna;Laender, Nora;Willcox, Carrie R.;Singh, Rohit;Schamel, Wolfgang W.;Nikolaev, Viacheslav O.;Kunzmann, Volker;Wiemer, Andrew J.;Willcox, Benjamin E.;Herrmann, Thomas
丁咯菲林(Btn)-3A和BTn2A1分子在T细胞受体(Tcr)介导的对微生物和肿瘤来源的磷酸抗原(PAg)的感知过程中控制人Vγ9Vδ2T细胞的激活。然而，控制PAg传感的分子规则仍然很大程度上是未知的。在这里，我们建立了PAg介导的γδT细胞激活的三个机制原理。首先，在人类中，PAG与细胞内BTN3A1-B30.2结构域结合后，Vγ9Vδ2TCR触发涉及BTN3A2/BTN3A3的细胞外V结构域。此外，这两个蛋白结构域都位于BTN3A同源或异构体的不同链上，这对于PAg介导的有效激活是必不可少的。第二，BTN3A同或异构体的形成是由BTN3A链的膜旁区域之间的分子相互作用控制的，这些异构体在细胞内的转运和构象不同。最后，PAg不仅能够简单地与BTN3A-B30.2结合，而且能够促进其随后与BTN2A1-B30.2结构域的相互作用，这对于T细胞的激活是必不可少的。确定BTN蛋白中的这些合作决定因素和分工可以提高我们对PAG感知的理解，并阐明一种可能适用于BTN家族其他成员的作用模式。已知γδT细胞在丁亲素(Btn)的背景下识别磷抗原，但这一现象背后的分子规则尚不清楚。在这里，作者证明了BTN3A复合体中B30.2和IGV结构域的不同拓扑结构促进了抗原感知，而膜旁区域控制着BTN复合体的形成。
Butyrophilin (BTN)–3A and BTN2A1 molecules control the activation of human Vγ9Vδ2 T cells during T cell receptor (TCR)-mediated sensing of phosphoantigens (PAg) derived from microbes and tumors. However, the molecular rules governing PAg sensing remain largely unknown. Here, we establish three mechanistic principles of PAg-mediated γδ T cell activation. First, in humans, following PAg binding to the intracellular BTN3A1-B30.2 domain, Vγ9Vδ2 TCR triggering involves the extracellular V-domain of BTN3A2/BTN3A3. Moreover, the localization of both protein domains on different chains of the BTN3A homo-or heteromers is essential for efficient PAg-mediated activation. Second, the formation of BTN3A homo-or heteromers, which differ in intracellular trafficking and conformation, is controlled by molecular interactions between the juxtamembrane regions of the BTN3A chains. Finally, the ability of PAg not simply to bind BTN3A-B30.2, but to promote its subsequent interaction with the BTN2A1-B30.2 domain, is essential for T-cell activation. Defining these determinants of cooperation and the division of labor in BTN proteins improves our understanding of PAg sensing and elucidates a mode of action that may apply to other BTN family members. γδ T cells are known to recognize phosphoantigen in the context of butyrophilins (BTN), yet the molecular rules underlying this phenomenon are unclear. Here, the authors demonstrate that a distinct topology of B30.2 and IgV domains within BTN3A complexes promotes antigen sensing and that the juxtamembrane region controls BTN complex formation.
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影响因子：
2.9
作者：
GRADDIS, TJ;MYSZKA, DG;CHAIKEN, IM
通讯作者：
CHAIKEN, IM
影响因子：
3.2
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Herrmann, Thomas
影响因子：
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Herrmann, Thomas
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通讯作者：
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影响因子：
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作者：
Barros, Rafael Di Marco;Roberts, Natalie A.;Dart, Robin J.;Vantourout, Pierre;Jandke, Anett;Nussbaumer, Oliver;Deban, Livija;Cipolat, Sara;Hart, Rosie;Iannitto, Maria Luisa;Laing, Adam;Spencer-Dene, Bradley;East, Philip;Gibbons, Deena;Irving, Peter M.;Pereira, Pablo;Steinhoff, Ulrich;Hayday, Adrian
通讯作者：
Hayday, Adrian