Post-Transcriptional Regulation of Interleukin-7 Receptor Expression

IL-7受体表达和信号传导对于常规T细胞至关重要，但是IL-7受体表达和信号传导对于常规T细胞至关重要。 IL-7受体在先天性T细胞中的作用还不太清楚。具体来说，IL-7 需要不变的NKT（iNKT）细胞，这是胸腺衍生的效应T细胞群， 在炎症和癌症中发挥有效调节作用的细胞仍然不清楚。我们 最近，我将我们的研究从传统的ab T细胞扩展到IL-7在iNKT中的作用 细胞，我们记录了iNKT细胞对IL-7的以前未被认识到的需求 体内平衡关于iNKT细胞的传统观点是，这种T细胞群是 它们的存活和维持主要依赖于IL-15信号传导，而IL-7仅 在这个过程中扮演了一个次要的角色。使用IL-15缺陷型小鼠并使用成年 胸腺切除的小鼠被植入IL-7或IL-15释放渗透泵， 现在证明是IL-7而不是IL-15控制iNKT细胞的稳态 在外周组织中（Park JY等人，2022，Cell Reports）。这些结果建立了新的 在成熟iNKT细胞上表达IL-7 R的需要，从而扩大了IL-7在T细胞中的作用。 细胞生物学其他先天性T细胞，如MAIT细胞，PLZF+ gd T细胞， 胸腺先天性CD 8 T细胞也需要IL-7 R表达，并且它们的稳态信号传导是 我们不清楚，但我们的目标是在我们未来的研究中解决这些问题。沿着这些路线， 我们还评估了IL-7对非淋巴组织中ab T细胞的作用，包括 肝、肺和小肠上皮（SI）。SI上皮内 淋巴细胞（IEL）相当于体内最大的T细胞库，它们是 被认为在维持免疫监视和静止中起关键作用， 直觉在这里，我们发现SI IEL在其存活所需的细胞因子方面有所不同，因此， 它们大多不依赖于IL-7，并且它们也不能对IL-7应答。的分子基础 IL-7非依赖性的SIIEL T细胞的稳态是目前的一个主要问题， 在这个项目中，我们正在测试SI上皮细胞的假设， 微环境会提供这些生存线索。对此，我们近日报道 Foxp 3 Treg细胞需要IL-2来维持其存活和效应功能， 一旦它们进入S1上皮，就从它们的IL-2需要中释放（Prakhar P.等，2021年，JCI 见解）。总的来说，这些结果表明，细胞因子的作用和要求， 根据组织而不同，并且需要考虑组织环境 当评估给定细胞因子的个体作用时。最后，我们发起了一系列 IL-7受体表达调节机制的新研究，我们也讨论了 IL-7 R表达的表观遗传学方面。具体来说，我们正在评估染色质的作用， 重构锌指转录因子Ikaros（Ikfz 1）作为一种新的调控因子， IL-7 Ra基因位点的可及性。因此，我们发现Ikfz 1控制IL-7 Ra 在胸腺中的早期T细胞发育期间和在存活/稳态中的表达 外周血T细胞为了进一步了解Ikaros如何促进细胞因子受体 调节一般，特别是IL-7 Ra表达，我们已经产生了一系列的 Ikfz 1条件性敲除小鼠，其中Ikfz 1-floxed小鼠与CD 2-Cre杂交 重组酶转基因小鼠或CD 4-Cre转基因小鼠等。与此同时，我们也 制备Ikfz 1转基因小鼠，以测试Ikfz 1过表达对T细胞的影响， 在IL-7 R信号传导的背景下的生成和稳态。分析T细胞发育 这些小鼠在IL-7 R表达背景下的分化目前正在研究中。 调查

IL-7 receptor expression and signaling is ciritical for conventional T cells, but the role of IL-7 receptor in innate-like T cells is less well understood. Specifically, the IL-7 requirement for invariant NKT (iNKT) cells, which is a thymus-derived population of effector T cells that plays potent regulatory roles in inflammation and cancer, has remained unclear. We have recently expanded our studies from conventional ab T cells into the role of IL-7 in iNKT cells, and we documented a previously unappreciated requirement for IL-7 in iNKT cell homeostasis. The conventional view on iNKT cells has been that this T cell population is mostly dependent on IL-15 signaling for their survival and maintenance, and that IL-7 only plays a minor role in this process. Using IL-15-deficient mice and employing adult thymectomized mice that were implanted with either IL-7- or IL-15-releasing osmotic pumps, we now demonstrated that it is IL-7, and not IL-15, that controls the homeostasis of iNKT cells in peripheral tissues (Park JY et al., 2022, Cell Reports). These results establish a new requirement for IL-7R expression on mature iNKT cells, thus expanding the role of IL-7 in T cell biology. Whether other innate-like T cells, such as MAIT cells, PLZF+ gd T cells, and thymic innate CD8 T cells also require IL-7R expression and signaling for their homeostasis is not clear to us, but we aim to address these issues in our future studies. Along these lines, we have also assessed the role of IL-7 on ab T cells in non-lymphoid tissues, including the liver, lung, and the epithelium of the small intestine (SI). The SI intra-epithelial lymphocytes (IELs) correspond to the largest reservoir of T cells in the body, and they are considered to play critical roles in maintaining immune surveillance and quiescence in the gut. Here, we found that SI IELs differ in their cytokine requirement for survival, so that they are mostly independent of IL-7, and they also cannot respond to IL-7. The molecular basis of the IL-7-independent homeostasis of SI IEL T cells is currently a major question that we are addressing in this project, and we are testing the hypothesis that the SI epithelial microenvironment would be providing these survival cues. In this regard, we recently reported that Foxp3 Treg cells, which need IL-2 for their survival and effector function, are exempt from their IL-2 requirement once they enter the SI epithelium (Prakhar P. et al., 2021, JCI Insights). Collectively, these results indicated that the role and requirement for cytokines differ depending on the tissue, and that the tissue environment needs to be taken into account when assessing the individual role of a given cytokine. Finally, we have initiated a series of new studies on the regulatory mechanisms of IL-7 receptor expression where we also address the epigenetic aspect of IL-7R expression. Specifically, we are assessing a role for the chromatin remodeling zinc finger transcription factor Ikaros (Ikfz1) as a novel regulator of controlling the accessibility of IL-7Ra gene locus. As such, we found that Ikfz1 controls IL-7Ra expression during the early T cell development in the thymus and in the survival/homeostasis of peripheral T cells. To further understand how Ikaros contributes to cytokine receptor regulation in general, and specifically to IL-7Ra expression, we have generated a series of Ikfz1-conditional knock out mice whereby Ikfz1-floxed mice were crossed with CD2-Cre recombinase transgenic mice or CD4-Cre transgenic mice, among others. In parallel, we also generated Ikfz1 transgenic mice to test the effect of Ikfz1 overexpression on T cell generation and homeostasis in the context of IL-7R signaling. Analyzing the T cell development and differentiation of these mice in context of IL-7R expression is currently under investigation.