NKG2A is a late immune checkpoint on CD8 T cells and marks repeated stimulation and cell division.
NKG2A is a late immune checkpoint on CD8 T cells and marks repeated stimulation and cell division.
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NKG2A是CD8 T细胞的晚期免疫检查点，并标记重复刺激和细胞分裂。
DOI：
10.1002/ijc.33859
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发表时间：
2022-02-15
影响因子：
6.4
通讯作者：
中科院分区：
文献类型：
--
作者：
表面抑制性受体NKG 2A与不变的CD 94链形成异二聚体，并在活化的CD 8 T细胞亚群上表达。由于阻断NKG 2A的抗体目前在几项针对不同肿瘤适应症的疗效试验中进行了检测，因此在其他抑制性受体的背景下表征NKG 2A + CD 8 T细胞群非常重要。在这里，我们使用了一个良好控制的培养系统来研究抑制性受体表达的动力学。在稳态细胞因子IL-7的存在下，通过人工抗原呈递细胞同步且重复地激活幼稚小鼠CD 8 T细胞。结果显示NKG 2A是一种晚期抑制性受体，在重复同源抗原刺激后表达。相比之下，PD-1、TIGIT和LAG-3的表达在首次接触后数小时迅速诱导，随后在每个静息期下调。NKG 2A的这种晚期但稳定的表达动力学与TIM-3和CD 39的表达动力学最相似。重要的是，人类肿瘤浸润淋巴细胞（TIL）的单细胞转录组学显示，这些受体通常由相同的CD 8 T细胞簇共表达。此外，NKG 2A表达与细胞分裂相关，并在体外由TGF-β促进，尽管TGF-β信号传导在体内小鼠肿瘤模型中不是必需的。总之，我们的数据表明PD-1反映了最近的TCR触发，但NKG 2A是在重复抗原刺激后诱导的，代表一种晚期抑制性受体。因此，NKG 2A与TIM-3和CD 39一起可能标记活跃分裂的肿瘤特异性TIL。 有什么新消息吗？ 免疫抑制受体NKG 2A在癌症免疫治疗中引起了新的关注，靶向和中断NKG 2A的抗体与PD-L1阻断剂联合使用，在正在进行的临床试验中产生了有希望的抗肿瘤反应。然而，CD 8 T细胞上的NKG 2A表达尚未完全绘制，因此对其调控知之甚少。在此，抑制性受体表达动力学的体外分析将NKG 2A鉴定为晚期免疫检查点。它的表达，在反复抗原接触后诱导，通常与TIM 3和CD 39相关。研究结果表明，NKG 2A是识别肿瘤特异性T细胞的潜在标志物。
The surface inhibitory receptor NKG2A forms heterodimers with the invariant CD94 chain and is expressed on a subset of activated CD8 T cells. As antibodies to block NKG2A are currently tested in several efficacy trials for different tumor indications, it is important to characterize the NKG2A+ CD8 T cell population in the context of other inhibitory receptors. Here we used a well‐controlled culture system to study the kinetics of inhibitory receptor expression. Naïve mouse CD8 T cells were synchronously and repeatedly activated by artificial antigen presenting cells in the presence of the homeostatic cytokine IL‐7. The results revealed NKG2A as a late inhibitory receptor, expressed after repeated cognate antigen stimulations. In contrast, the expression of PD‐1, TIGIT and LAG‐3 was rapidly induced, hours after first contact and subsequently down regulated during each resting phase. This late, but stable expression kinetics of NKG2A was most similar to that of TIM‐3 and CD39. Importantly, single‐cell transcriptomics of human tumor‐infiltrating lymphocytes (TILs) showed indeed that these receptors were often coexpressed by the same CD8 T cell cluster. Furthermore, NKG2A expression was associated with cell division and was promoted by TGF‐β in vitro, although TGF‐β signaling was not necessary in a mouse tumor model in vivo. In summary, our data show that PD‐1 reflects recent TCR triggering, but that NKG2A is induced after repeated antigen stimulations and represents a late inhibitory receptor. Together with TIM‐3 and CD39, NKG2A might thus mark actively dividing tumor‐specific TILs. What's new? The immune inhibitory receptor NKG2A is of emerging interest in cancer immunotherapy, with antibodies that target and interrupt NKG2A, in combination with PD‐L1 blockade, yielding promising antitumor responses in ongoing clinical trials. NKG2A expression on CD8 T cells, however, has not been fully charted and thus little is known about its regulation. Here, in vitro analyses of the kinetics of inhibitory receptor expression identify NKG2A as a late immune checkpoint. Its expression, induced upon repeated antigen encounter, is frequently associated with TIM3 and CD39. The findings suggest that NKG2A is a potential marker for the identification of tumor‐specific T cells.
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影响因子：
5.4
作者：
Anderson, Ana C.;Lord, Graham M.;Dardalhon, Valerie;Lee, David H.;Sabatos-Peyton, Catherine A.;Glimcher, Laurie H.;Kuchroo, Vijay K.
通讯作者：
Kuchroo, Vijay K.
影响因子：
46.9
作者：
Becht, Etienne;McInnes, Leland;Newell, Evan W.
通讯作者：
Newell, Evan W.
影响因子：
64.5
作者：
André P;Denis C;Soulas C;Bourbon-Caillet C;Lopez J;Arnoux T;Bléry M;Bonnafous C;Gauthier L;Morel A;Rossi B;Remark R;Breso V;Bonnet E;Habif G;Guia S;Lalanne AI;Hoffmann C;Lantz O;Fayette J;Boyer-Chammard A;Zerbib R;Dodion P;Ghadially H;Jure-Kunkel M;Morel Y;Herbst R;Narni-Mancinelli E;Cohen RB;Vivier E
通讯作者：
Vivier E
影响因子：
9.3
作者：
Bernstein, Nicholas J.;Fong, Nicole L.;Kelley, David R.
通讯作者：
Kelley, David R.
影响因子：
20.3
作者：
Cho, Jae-Ho;Kim, Hee-Ok;Sprent, Jonathan
通讯作者：
Sprent, Jonathan