ADAP plays a pivotal role in CD4+ T cell activation but is only marginally involved in CD8+ T cell activation, differentiation, and immunity to pathogens
ADAP plays a pivotal role in CD4+ T cell activation but is only marginally involved in CD8+ T cell activation, differentiation, and immunity to pathogens
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DOI：
10.1189/jlb.1a0216-090rr
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发表时间：
2017-02
影响因子：
5.5
通讯作者：
G. Parzmair;M. Gereke;Oxana Haberkorn;M. Annemann;Lisa Podlasly;S. Kliche;A. Reinhold;B. Schraven;D. Bruder
中科院分区：
文献类型：
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作者：
G. Parzmair;M. Gereke;Oxana Haberkorn;M. Annemann;Lisa Podlasly;S. Kliche;A. Reinhold;B. Schraven;D. Bruder
粘附和脱颗粒促进接头蛋白（ADAP）是一种多功能支架，参与许多不同的信号通路，这些信号通路对T细胞的功能很重要，包括整合素的内向外和外向内信号传导，NF - κB的激活，以及随后的促炎细胞因子（如IFN - γ和IL - 2）的产生。值得注意的是，尽管ADAP在T细胞中的作用已得到证实，但先前的研究并未区分CD4+和CD8+ T细胞，因此，尚不清楚ADAP是否在这两种T细胞亚群中发挥同样重要的功能。我们在这里表明，尽管ADAP在CD4+和CD8+ T细胞中的表达水平相当，但它们的功能依赖于ADAP的差异。体外TCR刺激实验显示，缺乏ADAP的CD4+ T细胞的活化、增殖和粘附受到严重损害，而缺乏ADAP的CD8+ T细胞几乎不受影响。因此，在单核增生李斯特菌（Listeria monocytogenes, Lm）和甲型流感病毒（influenza A virus， IAV）感染期间，对过过转移的CD8+ T细胞进行抗原特异性体内刺激显示，ADAP缺乏在CD8+ T细胞活化、增殖和分化方面只有中等影响，但不会损害病原体特异性免疫。因此，我们首次发现ADAP在CD4+和CD8+ T细胞中实现不同的功能，CD8+ T细胞对ADAP的依赖性较小。我们的数据确定ADAP是T细胞亚群特异性治疗干预的潜在分子靶点。
The adhesion and degranulation promoting adaptor protein (ADAP) is a multifunctional scaffold involved in many different signaling pathways that are important for the function of T cells, including the inside‐out and outside‐in signaling of integrins, the activation of NF‐κB, and the subsequent production of proinflammatory cytokines (e.g., IFN‐γ and IL‐2). Strikingly, despite its well‐established role in T cells, previous studies did not distinguish between CD4+ and CD8+ T cells, and thus, it is unknown whether ADAP fulfills equally important functions in both T cell subsets. We show here that despite comparable ADAP expression levels in CD4+ and CD8+ T cells, their function is differentially dependent on ADAP. Whereas in vitro TCR‐stimulation experiments revealed that activation, proliferation, and adhesion are severely compromised in CD4+ T cells lacking ADAP, their CD8+ counterparts are hardly affected by ADAP deficiency. Accordingly, antigen‐specific in vivo stimulation of adoptively transferred CD8+ T cells during Listeria monocytogenes (Lm) and influenza A virus (IAV) infection revealed only moderate effects of ADAP deficiency in terms of CD8+ T cell activation, proliferation, and differentiation, which, however, did not impair pathogen‐specific immunity. Thus, we show for the first time that ADAP fulfills different functions in CD4+ and CD8+ T cells, with CD8+ T cells being less dependent on ADAP. Our data identify ADAP as a potential molecular target for T cell subset‐specific therapeutic interventions.