Ovalbumin Antigen-Specific Activation of Human T Cell Receptor Closely Resembles Soluble Antibody Stimulation as Revealed by BOOST Phosphotyrosine Proteomics.
Ovalbumin Antigen-Specific Activation of Human T Cell Receptor Closely Resembles Soluble Antibody Stimulation as Revealed by BOOST Phosphotyrosine Proteomics.
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DOI：
10.1021/acs.jproteome.1c00239
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发表时间：
2021-06-04
影响因子：
4.4
通讯作者：
Salomon A
中科院分区：
文献类型：
--
作者：
Chua XY;Salomon A
T细胞受体（TCR）的活化导致主要由T细胞中的酪氨酸磷酸化协调的早期信号传导网络。TCR通常使用可溶性抗TCR抗体激活，但这种方法不是抗原特异性的。或者，使用肽-主要组织相容性复合物（pMHC）形式的一系列结合亲和力的特异性抗原激活TCR被认为是更生理性的。然而，由于缺乏大规模的磷酸酪氨酸（pTyr）蛋白质组学研究直接比较抗TCR抗体和pMHC，这些激活状态的全面定义仍然是谜。使用定量pTyr蛋白质组学对酪氨酸磷酸化蛋白质组进行阐明，能够更好地理解这些活化剂的独特特征以及配体结合亲和力对信号传导的作用。在这里，我们应用最近建立的广谱优化选择性触发（BOOST），以检查干扰的酪氨酸磷酸化的人TCR触发的抗TCR抗体和pMHC。我们的数据揭示，与抗TCR抗体相比，人TCR的高亲和力卵清蛋白（OVA）pMHC激活触发了很大程度上类似的，尽管可能更强的pTyr介导的信号传导调节轴。由OVA pMHC变体产生的信号输出与它们较弱的亲和力很好地相关，使得能够对信号强度进行亲和力可调的控制。总的来说，我们提供了一个框架，应用BOOST比较pTyr介导的信号通路的人T细胞激活的抗原非依赖性和抗原特异性的方式。@xienyuChua很好地展示了BOOST磷酸酪氨酸蛋白质组学的生物学效用。本研究为比较不同活化剂触发的T细胞受体信号通路提供了一个框架。
Activation of T cell receptors (TCR) leads to a network of early signaling predominantly orchestrated by tyrosine phosphorylation in T cells. TCR are commonly activated using soluble anti-TCR antibodies, but this approach is not antigen-specific. Alternatively, activating the TCR using specific antigens of a range of binding affinities in the form of peptide-major histocompatibility complex (pMHC) is presumed to be more physiological. However, due to the lack of wide-scale phosphotyrosine (pTyr) proteomic studies directly comparing anti-TCR antibodies and pMHC, a comprehensive definition of these activated states remains enigmatic. Elucidation of the tyrosine phosphoproteome using quantitative pTyr proteomics enables a better understanding of the unique features of these activating agents and the role of ligand binding affinity on signaling. Here, we apply the recently established Broad-spectrum Optimization Of Selective Triggering (BOOST) to examine perturbations in tyrosine phosphorylation of human TCR triggered by anti-TCR antibodies and pMHC. Our data reveals that high-affinity ovalbumin (OVA) pMHC activation of the human TCR triggers a largely similar, albeit potentially stronger, pTyr-mediated signaling regulatory axis compared to anti-TCR antibody. Signaling output resulting from OVA pMHC variants correlates well with their weaker affinities, enabling affinity-tunable control of signaling strength. Collectively, we provide a framework for applying BOOST to compare pTyr-mediated signaling pathways of human T cells activated in an antigen-independent and antigen-specific manner. @xienyuChua nicely demonstrated the biological utility of BOOST phosphotyrosine proteomics. This study provided a framework for comparing signaling pathways of T cell receptors triggered by different activators.
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