Department of Biology and Biotechnology Charles Darwin, Sapienza University, Rome, Italy.
Laboratory affiliated to Istituto Pasteur Italia-Fondazione Cenci Bolognetti, Sapienza University, Rome, Italy.
Front Immunol. 2020 Oct 14;11:590964. doi: 10.3389/fimmu.2020.590964. eCollection 2020.
IL-22 is a member of the IL-10 cytokine family involved in host protection against extracellular pathogens, by promoting epithelial cell regeneration and barrier functions. Dysregulation of IL-22 production has also frequently been observed in acute respiratory distress syndrome (ARDS) and several chronic inflammatory and autoimmune diseases. We have previously described that human CD28, a crucial co-stimulatory receptor necessary for full T cell activation, is also able to act as a TCR independent signaling receptor and to induce the expression of IL-17A and inflammatory cytokines related to Th17 cells, which together with Th22 cells represent the main cellular source of IL-22. Here we characterized the role of CD28 autonomous signaling in regulating IL-22 expression in human CD4 T cells. We show that CD28 stimulation in the absence of TCR strongly up-regulates IL-22 gene expression and secretion. As recently observed for IL-17A, we also found that CD28-mediated regulation of IL-22 transcription requires the cooperative activities of both IL-6-activated STAT3 and RelA/NF-κB transcription factors. CD28-mediated IL-22 production also promotes the barrier functions of epithelial cells by inducing mucin and metalloproteases expression. Finally, by using specific inhibitory drugs, we also identified CD28-associated class 1A phosphatidylinositol 3-kinase (PI3K) as a pivotal mediator of CD28-mediated IL-22 expression and IL-22-dependent epithelial cell barrier functions.
白细胞介素-22 (IL-22) 是白细胞介素-10 细胞因子家族的一员，通过促进上皮细胞再生和屏障功能，参与宿主对细胞外病原体的保护。白细胞介素-22 产生的失调也经常在急性呼吸窘迫综合征 (ARDS) 和几种慢性炎症和自身免疫性疾病中观察到。我们之前曾描述过，人类 CD28，一种充分激活 T 细胞所必需的关键共刺激受体，也能够作为 TCR 非依赖性信号受体发挥作用，并诱导白细胞介素-17A 和与 Th17 细胞相关的炎症细胞因子的表达，Th17 细胞和 Th22 细胞共同代表了白细胞介素-22 的主要细胞来源。在这里，我们描述了 CD28 自主信号在调节人类 CD4 T 细胞中白细胞介素-22 表达中的作用。我们表明，在没有 TCR 的情况下，CD28 的刺激强烈地上调了白细胞介素-22 基因的表达和分泌。与最近观察到的白细胞介素-17A 一样，我们还发现 CD28 介导的白细胞介素-22 转录的调节需要 IL-6 激活的 STAT3 和 RelA/NF-κB 转录因子的协同作用。CD28 介导的白细胞介素-22 产生也通过诱导粘蛋白和金属蛋白酶的表达来促进上皮细胞的屏障功能。最后，通过使用特异性抑制药物，我们还确定了与 CD28 相关的 1 类磷酸肌醇 3-激酶 (PI3K) 作为 CD28 介导的白细胞介素-22 表达和白细胞介素-22 依赖性上皮细胞屏障功能的关键介质。
