Negative regulation by PD-L1 during drug-specific priming of IL-22-secreting T cells and the influence of PD-1 on effector T cell function.
Negative regulation by PD-L1 during drug-specific priming of IL-22-secreting T cells and the influence of PD-1 on effector T cell function.
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DOI：
10.4049/jimmunol.1302720
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发表时间：
2014-03-15
期刊：
影响因子：
--
通讯作者：
Naisbitt DJ
中科院分区：
文献类型：
--
作者：
Gibson A;Ogese M;Sullivan A;Wang E;Saide K;Whitaker P;Peckham D;Faulkner L;Park BK;Naisbitt DJ
T细胞上PD-1的活化被认为抑制抗原特异性T细胞引发并调节T细胞分化。因此，我们试图测量在PD-L1/2/PD-1结合扰动后初始T细胞的药物特异性活化，并研究PD-1信号传导是否影响T细胞的分化。当PD-L1信号传导被阻断时，发现针对药物抗原的幼稚CD 4+和CD 8 + T细胞的引发更有效。再刺激后，T细胞增殖更活跃，分泌的IFN-γ、IL-13和IL-22水平增加，但IL-17水平不变。初始T细胞表达低水平的PD-1;然而，在药物特异性T细胞引发期间观察到PD-1表达的瞬时增加。接下来，测量来自体外致敏的T细胞克隆和来自过敏患者的克隆的药物特异性应答，并将其与PD-1表达相关联。发现所有克隆分泌IFN-γ、IL-5和IL-13。更详细的分析揭示了两种不同的细胞因子特征。克隆分泌FasL/IL-22或颗粒酶B。FasL/IL 22分泌克隆表达皮肤归巢受体CCR 4、CCR 10和CLA，并响应于CCL 17/CCL 27而迁移。PD-1在克隆上以不同水平稳定表达;然而，PD-1表达与抗原特异性增殖反应的强度或细胞因子/细胞溶解分子的分泌无关。该研究表明，PD-L1/PD-1结合负调节药物特异性T细胞的引发。ELIspot分析揭示了具有皮肤归巢特性的抗原特异性FasL/IL-22分泌T细胞亚群。
Activation of PD-1 on T-cells is thought to inhibit antigen-specific T-cell priming and regulate T-cell differentiation. Thus, we sought to measure the drug-specific activation of naïve T-cells after perturbation of PD-L1/2/PD-1 binding and investigate whether PD-1 signaling influences the differentiation of T-cells. Priming of naïve CD4+ and CD8+ T-cells against drug antigens was found to be more effective when PD-L1 signaling was blocked. Upon restimulation, T-cells proliferated more vigorously and secreted increased levels of IFN-γ, IL-13 and IL-22, but not IL-17. Naïve T-cells expressed low levels of PD-1; however, a transient increase in PD-1 expression was observed during drug-specific T-cell priming. Next, drug-specific responses from in vitro primed T-cell clones and clones from hypersensitive patients were measured and correlated with PD-1 expression. All clones were found to secrete IFN-γ, IL-5 and IL-13. More detailed analysis revealed two different cytokine signatures. Clones secreted either FasL/IL-22 or granzyme B. The FasL/IL22 secreting clones expressed the skin homing receptors CCR4, CCR10 and CLA and migrated in response to CCL17/CCL27. PD-1 was stably expressed at different levels on clones; however, PD-1 expression did not correlate with the strength of the antigen-specific proliferative response or the secretion of cytokines/cytolytic molecules. This study shows that PD-L1/PD-1 binding negatively regulates the priming of drug-specific T-cells. ELIspot analysis uncovered an antigen-specific FasL/IL-22 secreting T-cell subset with skin homing properties.
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DOI：
10.1016/j.jaci.2010.11.046
发表时间：
2011-03
期刊：
The Journal of allergy and clinical immunology
影响因子：
--
作者：
Phillips EJ;Chung WH;Mockenhaupt M;Roujeau JC;Mallal SA
通讯作者：
Mallal SA
影响因子：
17.1
作者：
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通讯作者：
Musette, Philippe
影响因子：
32.4
作者：
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通讯作者：
Freeman, Gordon J.
影响因子：
3.8
作者：
Faulkner, Lee;Martinsson, Klara;Park, B. Kevin
通讯作者：
Park, B. Kevin
影响因子：
2
作者：
Jenkins, Rosalind E.;Meng, Xiaoli;Park, B. Kevin
通讯作者：
Park, B. Kevin