Nanoscale Colocalization of NK Cell Activating and Inhibitory Receptors Controls Signal Integration.
Nanoscale Colocalization of NK Cell Activating and Inhibitory Receptors Controls Signal Integration.
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DOI：
10.3389/fimmu.2022.868496
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发表时间：
2022
影响因子：
7.3
通讯作者：
中科院分区：
文献类型：
--
作者：
自然杀伤（NK）细胞反应依赖于抑制和激活受体信号的平衡。然而，NK细胞-靶细胞相互作用中拮抗信号的整合是如何发生的尚不完全清楚。在这里，我们提供的证据表明，NK细胞通过抑制受体Ly49A的抑制依赖于其在纳米尺度上与激活受体NKG2D在免疫突触（is）形成时的相对共定位。使用表达NKG2D- gfp和Ly49A- rfp的原代NK细胞研究NKG2D和Ly49A信号整合和共定位，与NIH3T3靶细胞形成ISs，表达或不表达单链三聚体（SCT） H2-Dd和SCT H2-Dd- cd4 MHC-I分子的扩展形式。通过Förster NKG2D-GFP和Ly49A-RFP之间的共振能量转移来评估纳米尺度的共定位，并测量每个突触的共定位。在各自同源配体存在的情况下，NKG2D和Ly49A在纳米尺度上共定位，导致NK细胞抑制。然而，增加Ly49A配体的大小减少了与NKG2D的纳米级共定位，从而损害了Ly49A介导的抑制作用。因此，我们的数据表明NK细胞信号整合严重依赖于NK细胞配体-受体对的尺寸，通过影响它们在is的相对纳米尺度共定位。我们的研究结果表明，NK细胞信号和NK细胞反应的平衡是由免疫突触中激活和抑制受体的相对纳米级共定位决定的。
Natural killer (NK) cell responses depend on the balance of signals from inhibitory and activating receptors. However, how the integration of antagonistic signals occurs upon NK cell–target cell interaction is not fully understood. Here we provide evidence that NK cell inhibition via the inhibitory receptor Ly49A is dependent on its relative colocalization at the nanometer scale with the activating receptor NKG2D upon immune synapse (IS) formation. NKG2D and Ly49A signal integration and colocalization were studied using NKG2D-GFP and Ly49A-RFP-expressing primary NK cells, forming ISs with NIH3T3 target cells, with or without the expression of single-chain trimer (SCT) H2-Dd and an extended form of SCT H2-Dd-CD4 MHC-I molecules. Nanoscale colocalization was assessed by Förster resonance energy transfer between NKG2D-GFP and Ly49A-RFP and measured for each synapse. In the presence of their respective cognate ligands, NKG2D and Ly49A colocalize at the nanometer scale, leading to NK cell inhibition. However, increasing the size of the Ly49A ligand reduced the nanoscale colocalization with NKG2D, consequently impairing Ly49A-mediated inhibition. Thus, our data shows that NK cell signal integration is critically dependent on the dimensions of NK cell ligand–receptor pairs by affecting their relative nanometer-scale colocalization at the IS. Our results together suggest that the balance of NK cell signals and NK cell responses is determined by the relative nanoscale colocalization of activating and inhibitory receptors in the immune synapse.
影响因子：
3.7
作者：
Schleinitz N;March ME;Long EO
通讯作者：
Long EO
影响因子：
14.8
作者：
通讯作者：
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DOI：
10.1084/jem.184.6.2243
发表时间：
1996-12-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Valiante NM;Phillips JH;Lanier LL;Parham P
通讯作者：
Parham P