探討第四型腺苷酸激酶在輔助性第二、第十七型及調節性T細胞中扮演的角色

Abstract

第二型輔助型T細胞主要的免疫功能是：釋放細胞素吸引嗜酸性球和肥大細胞，並促進這些細胞增殖以抵抗寄生蟲等胞外病原體。第十七型輔助型T細胞主要是扮演胞外細菌的清除者；然而，過度的第十七型輔助型T細胞免疫反應會造成自體免疫反應。調節型T細胞透過分泌抑制性的細胞素，或是競爭使用介白素-2等方式以調節輔助型T細胞的功能。第四型腺苷酸激酶位於粒腺體內，主要的功能是平衡細胞質中的單磷酸、二磷酸及三磷酸腺苷的濃度；有報導指出第四型腺苷酸激酶還具有將粒腺體內的三磷酸腺苷運送到細胞質的能力。過去我們實驗室證明第四型腺苷酸激酶在基因減弱下，促進第一型輔助型T細胞的γ型干擾素分泌。本實驗證明第四型腺苷酸激酶的基因減弱，可促使第二型輔助型T細胞的介白素-4,-5,-13和第十七型輔助型T細胞的介白素-17A,-21分泌量提升。但是，第四型腺苷酸激酶的基因減弱會降低介白素-10的分泌量。而丙酮酸脫氫酶可能是第四型腺苷酸激酶潛在的下游代謝調控者，於第四型腺苷酸激酶的基因減弱時表現量提升，同時促進輔助型T細胞的細胞素的產生。我們的研究推測第四型腺苷酸在T細胞中可能扮演維持三羧酸循環的功能，並且調節輔助型T細胞的細胞素分泌。

TH2 cells are known to confront extracellular pathogens such as parasites and helminths by mediating the proliferation and recruitment of eosinophils and mast cells. TH17 cells play a role in expelling extracellular bacteria. In addition, TH17 cells are involved in the pathogenesis of autoimmune disease. Regulatory T cells (TREG) limit the function of effector T cells by several mechanisms, including secreting inhibitory cytokines and competing for IL-2 with effector T cells. Adenylate kinase 4 (Ak4) in mitochondria regulates the homeostasis of AMP, ADP and ATP. It also controls the ATP transportation toward cytosol. Previous study in our laboratory showed that Ak4 knockdown (KD) promotes the expression of TH1 cytokine, IFN-γ. Here, we hypothesized that Ak4 regulates the function of TH2, TH17 and regulatory T cells. Our data showed that Ak4 KD in TH2 cells upregulated the expression of IL-4, IL-5 and IL-13. Moreover, Ak4 silencing promoted the secretion of IL-17A and IL-21 in TH17 cells. Conversely, the expression of IL-10 was compromised in induced regulatory T cells with Ak4 KD. We also identified pyruvate dehydrogenase kinase 1 as the potential metabolic mediator that upregulates the cytokine production in T helper cells. Our research illustrated that Ak4 may promote the function of TCA cycle and further negatively regulate the function of T helper cells.