Fine-tuning innate and adaptive immune responses: another KLFhanger. Focus on "Krüppel-like factor KLF10 regulates transforming growth factor receptor II expression and TGF-β signaling in CD8+ T lymphocytes".
Fine-tuning innate and adaptive immune responses: another KLFhanger. Focus on "Krüppel-like factor KLF10 regulates transforming growth factor receptor II expression and TGF-β signaling in CD8+ T lymphocytes".
复制标题
微调先天性和适应性免疫反应：另一个 KLFhanger。
DOI：
10.1152/ajpcell.00418.2014
复制
发表时间：
2015
期刊：
影响因子：
--
通讯作者：
Feinberg,MarkW
中科院分区：
文献类型：
--
作者：
Feinberg,MarkW
免疫系统失调可能导致一系列疾病，如自身免疫、慢性炎症性疾病、移植排斥或癌症。为了应对外来病原体，后生动物进化出了两层防线——先天免疫系统和适应性免疫系统。当微生物（例如，通过双链RNA或脂多糖）被高度保守的病原体相关分子模式（也称为模式识别受体）识别时，通常会触发宿主的第一道防线。然而，这种水平的防御是相当非特异性的，通常不会赋予持久的免疫力。吞噬细胞如巨噬细胞、中性粒细胞或树突状细胞，以及肥大细胞和自然杀伤细胞（NK）不仅有助于消灭病原体，还可能参与激活适应性免疫系统。在抗原呈递过程中对特异性“非自身”抗原的识别促进了适应性反应，包括一系列T细胞和B细胞亚群，以产生特异性“记忆”细胞，使病原体再次暴露时能够更快地做出反应。CD8+ T细胞在急性和慢性微生物感染过程中参与宿主防御，并促进转化细胞的清除(3)。递呈短肽抗原的主要组织相容性复合体（MHC） I类分子与CD8+ T细胞（tcr）克隆受体的特异性相互作用足以触发诱导效应功能的信号事件。然而，越来越多的研究表明，CD8+ T细胞也可能介导不依赖抗原的效应反应（例如，不依赖于TCR特异性），当它们自身反应时，这种效应可能是有害的。最近的研究表明，组织常驻记忆CD8+ T细胞迅速诱导抗病毒状态，从而强调CD8+ T细胞具有先天和适应性免疫系统特性的能力(7)。因此，对CD8+ T细胞活化的精细控制和对抑制其反应的调节分子机制的理解，对调节与微生物病原体、抗肿瘤免疫、疫苗接种策略和慢性炎症疾病状态相关的先天和适应性免疫反应具有广泛的意义。在本期的《AJP-Cell》中，Papadakis等人(6)通过调节TGF-β受体II型（TGF-β rii）表达和下游TGF-β信号传导的能力，发现了一种新的CD8+ T细胞效应功能的转录调节因子，称为kr<s:1> pel样因子10 (KLF10)（图1）。TGF-β是一种控制一系列T细胞功能反应的多效生长因子(4)。事实上，携带T细胞特异性TGF-β受体缺失的小鼠会发生早期致命性多灶性炎症和自身免疫性疾病(4)。既往研究表明，TGF-β信号通过调节整合素α4 -β 7的表达，增加IL-7Rα的表达，诱导CD8+ T细胞分化，并使CD8+ T细胞效应物从脾脏向肠道等脏器迁移。而Papadakis等人(6)。与野生型（WT）小鼠相比，KLF10 J/J小鼠外周血CD8+ T细胞总数无显著差异，但CD8+ T细胞效应器与naïve T细胞的比例显著增加。有趣的是，TGF-βRII在活化/记忆和naïve KLF10 J/J CD8+ T细胞中的表达均显著降低。与这些发现一致，激活的KLF10 J/J CD8+ T细胞表现出更高的T-bet和IFN-γ表达，表明th1型免疫反应失调。值得注意的是，采用CD8+ KLF10 J过继转移1周后，Rag1 J/J小鼠的体内增殖试验。
DYSREGULATION OF THE IMMUNE SYSTEM may contribute to a range of conditions such as autoimmunity, chronic inflammatory disease, transplant rejection, or cancer. In response to foreign pathogens, metazoans have evolved to bear two layered lines of defense—the innate and adaptive immune system. The first line of host defense is typically triggered when microbial organisms (eg, by double-stranded RNA or lipopolysaccharide) are recognized by highly conserved pathogen-associated molecular patterns, also termed pattern recognition receptors. However, this level of defense is fairly nonspecific and does not usually confer long-lasting immunity. Phagocytic cells such as macrophages, neutrophils, or dendritic cells, as well as mast cells and natural killer (NK) cells not only facilitate eliminating pathogens, but also may participate in activating the adaptive immune system. Recognition of specific “nonself” antigens during antigen presentation facilitates the adaptive response comprising a range of T and B cell subsets to generate specific “memory” cells that enable a faster response upon pathogen reexposure. CD8+ T cells participate in host defense during acute and chronic microbial infection and also facilitate the elimination of transformed cells (3). The specific interaction of major histocompatibility complex (MHC) class I molecules presenting short peptide antigens to clonal receptors of CD8+ T cells (TCRs) is sufficient to trigger signaling events that induce effector functions. However, accumulating studies indicate that CD8+ T cells may also mediate antigen-independent effector responses (eg, independent of TCR specificity), an effect that could be harmful when they are self-reactive. Recent studies indicate that tissue resident memory CD8+ T cells rapidly induce an antiviral state, thereby highlighting that CD8+ T cells have the capacity to exhibit properties of both the innate and adaptive immune system (7). Consequently, exquisite control of CD8+ T cell activation and an understanding of the regulatory molecular mechanisms that dampen their response have broad implications for regulating both innate and adaptive immune responses associated with microbial pathogens, antitumor immunity, vaccination strategies, and chronic inflammatory disease states. In this issue of AJP-Cell, Papadakis et al.(6) identify a new transcriptional regulator of CD8+ T cell effector function termed Krüppel-like factor 10 (KLF10) by its ability to modulate the TGF-β receptor type II (TGF-βRII) expression and downstream TGF-β signaling (Fig. 1). TGF-β is a pleiotropic growth factor that controls an array of T cell functional responses (4). Indeed, mice harboring T cell-specific deletion of TGF-β receptors develop early fatal multifocal inflammatory and autoimmune disease (4). Previous studies indicate that TGF-β signaling induces CD8+ T cell differentiation by increasing IL-7Rα expression as well as emigration of CD8+ T cell effectors from the spleen to the organs such as the gut by regulating integrin α4β7 expression. While Papadakis et al.(6). found no differences in the total number of peripheral CD8+ T cells in KLF10 J/J mice compared with wild-type (WT) mice, the ratio of CD8+ T cell effectors to naïve T cells was markedly increased in KLF10 J/J mice. Interestingly, TGF-βRII expression was significantly reduced in both activated/memory and naïve KLF10 J/J CD8+ T cells. Consistent with these findings, activated KLF10 J/J CD8+ T cells exhibited higher expression of T-bet and IFN-γ, suggesting dysregulation of Th1-type immune responses. Remarkably, using in vivo proliferation assays in lymphopenic Rag1 J/J mice after 1 week of adoptive transfer of CD8+ KLF10 J …