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The lipid mediator PGE2 suppresses antitumor immunity by activating its four related GPCRs on T cells. Lone et al. used quantitative phosphoproteomics and phosphoflow cytometry to analyze downstream signaling elicited by the stimulation of all receptors simultaneously or individually in different T cell subsets. The analysis revealed G protein–dependent and G protein–independent pathways that were activated by each receptor in all T cells, as well as pathways that were activated by only a subset of receptors, in only a subset of cells, or with receptor-specific kinetics. Network modeling predicted mechanisms of cross-talk and signal integration downstream of the receptors. These data are a comprehensive resource for future explorations of the functional consequences of PGE2 receptor–specific signaling in immune homeostasis, inflammation, and tumor-associated immunosuppression.

脂質(zhì)介質(zhì) PGE 2通過激活 T 細(xì)胞上的四個(gè)相關(guān) GPCR 來抑制抗腫瘤免疫。孤獨(dú)等人。使用定量磷酸化蛋白質(zhì)組學(xué)和磷酸化流式細(xì)胞術(shù)來分析在不同 T 細(xì)胞亞群中同時(shí)或單獨(dú)刺激所有受體引起的下游信號(hào)傳導(dǎo)。分析揭示了由所有 T 細(xì)胞中的每個(gè)受體激活的 G 蛋白依賴性和 G 蛋白非依賴性通路，以及僅由一部分受體激活、僅在一部分細(xì)胞中或具有受體特異性的通路。動(dòng)力學(xué)。網(wǎng)絡(luò)建模預(yù)測(cè)了受體下游串?dāng)_和信號(hào)整合的機(jī)制。這些數(shù)據(jù)是未來探索 PGE 功能后果的綜合資源2免疫穩(wěn)態(tài)、炎癥和腫瘤相關(guān)免疫抑制中的受體特異性信號(hào)傳導(dǎo)。

5層細(xì)胞工廠

Prostaglandin E2 (PGE2) promotes an immunosuppressive microenvironment in cancer, partly by signaling through four receptors (EP1, EP2, EP3, and EP4) on T cells. Here, we comprehensively characterized PGE2 signaling networks in helper, cytotoxic, and regulatory T cells using a phosphoproteomics and phosphoflow cytometry approach. We identified ~1500 PGE2-regulated phosphosites and several important EP1–4 signaling nodes, including PKC, CK2, PKA, PI3K, and Src. T cell subtypes exhibited distinct signaling pathways, with the strongest signaling in EP2-stimulated CD8+ cells. EP2 and EP4, both of which signal through Gαs, induced similar signaling outputs, but with distinct kinetics and intensity. Functional predictions from the observed phosphosite changes revealed PGE2 regulation of key cellular and immunological processes. Last, network modeling suggested signal integration between the receptors and a substantial contribution from G protein–independent signaling. This study offers a comprehensive view of the different PGE2-regulated phosphoproteomes in T cell subsets, providing a valuable resource for further research on this physiologically and pathophysiologically important signaling system.

前列腺素 E 2 (PGE 2 ) 在癌癥中促進(jìn)免疫抑制微環(huán)境，部分是通過T 細(xì)胞上的四種受體（EP 1、EP 2、EP 3和 EP 4）傳遞信號(hào)。在這里，我們使用磷酸蛋白質(zhì)組學(xué)和磷酸流式細(xì)胞術(shù)方法全面表征了輔助性、細(xì)胞毒性和調(diào)節(jié)性 T 細(xì)胞中的PGE 2信號(hào)網(wǎng)絡(luò)。我們鑒定了約 1500 個(gè) PGE 2調(diào)節(jié)的磷酸位點(diǎn)和幾個(gè)重要的 EP 1-4信號(hào)節(jié)點(diǎn)，包括 PKC、CK2、PKA、PI3K 和 Src。T 細(xì)胞亞型表現(xiàn)出不同的信號(hào)通路，在 EP 2刺激的 CD8 + 中信號(hào)最強(qiáng)細(xì)胞。EP 2和EP 4均通過G αs發(fā)出信號(hào)，誘導(dǎo)類似的信號(hào)輸出，但具有不同的動(dòng)力學(xué)和強(qiáng)度。觀察到的磷位點(diǎn)變化的功能預(yù)測(cè)揭示了 PGE 2對(duì)關(guān)鍵細(xì)胞和免疫過程的調(diào)節(jié)。最后，網(wǎng)絡(luò)建模表明受體之間的信號(hào)整合和 G 蛋白非依賴性信號(hào)傳導(dǎo)的重要貢獻(xiàn)。這項(xiàng)研究提供了T 細(xì)胞亞群中不同 PGE 2調(diào)節(jié)的磷酸化蛋白質(zhì)組的綜合視圖，為進(jìn)一步研究這種在生理和病理生理上具有重要意義的信號(hào)系統(tǒng)提供了寶貴的資源。