Breaking Free of Control: How Conventional T Cells Overcome Regulatory T Cell Suppression.
Breaking Free of Control: How Conventional T Cells Overcome Regulatory T Cell Suppression.
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DOI：
10.3389/fimmu.2016.00193
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发表时间：
2016
影响因子：
7.3
通讯作者：
Lorenz UM
中科院分区：
文献类型：
--
作者：
Mercadante ER;Lorenz UM
传统的T(Tcon)细胞在形成免疫反应中是至关重要的，无论是对病原体的保护，对肿瘤细胞的细胞毒攻击，还是在自身免疫背景下对自身抗原的不想要的反应。在这些免疫环境中，调节性T细胞(Tregs)可以潜在地控制Tcon细胞的反应，导致Tcon细胞的抑制或激活。在生理条件下，Tcon细胞能够暂时克服Treg施加的限制，对感染威胁做出保护性反应，实现克隆扩增、分化和效应器功能。然而，近年来积累的证据表明，Tcon细胞对Treg介导的抑制的抵抗力在自身免疫性疾病的发病机制中起着重要作用。向另一个方向倾斜了太多的平衡，癌症肿瘤利用Tregs建立一个过度抑制的微环境，防止抗肿瘤Tcon细胞反应。鉴于Tcon/Treg相互作用的广泛临床重要性，本综述旨在更好地了解是什么决定了Tcon细胞是否对Treg介导的抑制敏感，以及这种微调平衡的扰动如何在病理条件下发挥作用。在这里，我们将重点关注使Tcon细胞对Treg抑制产生抵抗的一系列复杂的因素，我们将其分为两类：(1)细胞外因子介导的信号转导和(2)细胞内信号分子。进一步，我们探讨了操纵磷脂酰肌醇-3激酶(PI3K)/Akt信号通路的治疗意义，该信号通路被认为是介导Tcon抵抗抑制的信号通路的汇聚点。最后，我们解决了重要的悬而未决的问题，如获得抗性的时机和位置，以及“Treg抗性”表型的稳定性。
Conventional T (Tcon) cells are crucial in shaping the immune response, whether it is protection against a pathogen, a cytotoxic attack on tumor cells, or an unwanted response to self-antigens in the context of autoimmunity. In each of these immune settings, regulatory T cells (Tregs) can potentially exert control over the Tcon cell response, resulting in either suppression or activation of the Tcon cells. Under physiological conditions, Tcon cells are able to transiently overcome Treg-imposed restraints to mount a protective response against an infectious threat, achieving clonal expansion, differentiation, and effector function. However, evidence has accumulated in recent years to suggest that Tcon cell resistance to Treg-mediated suppression centrally contributes to the pathogenesis of autoimmune disease. Tipping the balance too far in the other direction, cancerous tumors utilize Tregs to establish an overly suppressive microenvironment, preventing antitumor Tcon cell responses. Given the wide-ranging clinical importance of the Tcon/Treg interaction, this review aims to provide a better understanding of what determines whether a Tcon cell is susceptible to Treg-mediated suppression and how perturbations to this finely tuned balance play a role in pathological conditions. Here, we focus in detail on the complex array of factors that confer Tcon cells with resistance to Treg suppression, which we have divided into two categories: (1) extracellular factor-mediated signaling and (2) intracellular signaling molecules. Further, we explore the therapeutic implications of manipulating the phosphatidylinositol-3 kinase (PI3K)/Akt signaling pathway, which is proposed to be the convergence point of signaling pathways that mediate Tcon resistance to suppression. Finally, we address important unresolved questions on the timing and location of acquisition of resistance, and the stability of the “Treg-resistant” phenotype.