Cytotoxic T Lymphocyte Activation Signals Modulate Cytoskeletal Dynamics and Mechanical Force Generation.
Cytotoxic T Lymphocyte Activation Signals Modulate Cytoskeletal Dynamics and Mechanical Force Generation.
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DOI：
10.3389/fimmu.2022.779888
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发表时间：
2022
影响因子：
7.3
通讯作者：
Upadhyaya A
中科院分区：
文献类型：
--
作者：
Pathni A;Özçelikkale A;Rey-Suarez I;Li L;Davis S;Rogers N;Xiao Z;Upadhyaya A
细胞毒性T淋巴细胞（CTL）通过杀死感染的细胞在适应性免疫应答中发挥不可或缺的作用。抗原呈递细胞（APC），如树突状细胞，将致病性肽呈递给CTL表面上的T细胞受体和完全活化所需的共刺激信号。活化的CTL分泌含有在CTL-靶标接触时触发靶细胞死亡的酶的裂解颗粒，也称为免疫突触（IS）。肌动蛋白和微管细胞骨架在杀伤CTL靶中起重要作用。溶解性颗粒沿着微管运输至IS，在IS处，颗粒分泌通过肌动蛋白消耗和恢复而促进。此外，肌动球蛋白收缩性通过介导IS处的机械力施加促进靶细胞死亡。最近的研究表明，由APC产生的炎性细胞因子，如白细胞介素-12（IL-12），作为CTL激活的第三信号，并增强CTL增殖和效应器功能。然而，介导这种增强的效应器功能的生物物理机制仍不清楚。我们假设，第三个信号CTL激活，IL-12，调节细胞骨架动力学和施力在IS，从而增强CTL效应功能。在这里，我们使用活细胞全内反射荧光（TIRF）显微镜研究肌动球蛋白和微管动力学在肽-MHC和共刺激单独（两个信号），或另外与IL-12（三个信号）的存在下激活的小鼠原代CTL的IS。我们发现，三个信号激活的细胞毒性T淋巴细胞有改变肌动蛋白流量，肌球蛋白动力学和微管生长速率相比，两个信号激活的细胞毒性T淋巴细胞。我们进一步表明，在三个信号激活的CTL中的溶解颗粒比在两个信号激活的CTL中更少聚集并且具有更低的速度。最后，我们使用牵引力显微镜显示，三个信号激活的CTL比两个信号激活的CTL施加更大的牵引力。我们的研究结果表明，在IL-12的存在下激活CTL导致细胞骨架的差异调节，从而增强CTL对其靶标的机械响应。这表明第三信号可以增强CTL应答的潜在物理机制。
Cytotoxic T lymphocytes (CTLs) play an integral role in the adaptive immune response by killing infected cells. Antigen presenting cells (APCs), such as dendritic cells, present pathogenic peptides to the T cell receptor on the CTL surface and co-stimulatory signals required for complete activation. Activated CTLs secrete lytic granules containing enzymes that trigger target cell death at the CTL-target contact, also known as the immune synapse (IS). The actin and microtubule cytoskeletons are instrumental in the killing of CTL targets. Lytic granules are transported along microtubules to the IS, where granule secretion is facilitated by actin depletion and recovery. Furthermore, actomyosin contractility promotes target cell death by mediating mechanical force exertion at the IS. Recent studies have shown that inflammatory cytokines produced by APCs, such as interleukin-12 (IL-12), act as a third signal for CTL activation and enhance CTL proliferation and effector function. However, the biophysical mechanisms mediating such enhanced effector function remain unclear. We hypothesized that the third signal for CTL activation, IL-12, modulates cytoskeletal dynamics and force exertion at the IS, thus potentiating CTL effector function. Here, we used live cell total internal reflection fluorescence (TIRF) microscopy to study actomyosin and microtubule dynamics at the IS of murine primary CTLs activated in the presence of peptide-MHC and co-stimulation alone (two signals), or additionally with IL-12 (three signals). We found that three signal-activated CTLs have altered actin flows, myosin dynamics and microtubule growth rates as compared to two signal-activated CTLs. We further showed that lytic granules in three-signal activated CTLs are less clustered and have lower velocities than in two-signal activated CTLs. Finally, we used traction force microscopy to show that three signal-activated CTLs exert greater traction forces than two signal-activated CTLs. Our results demonstrate that activation of CTLs in the presence of IL-12 leads to differential modulation of the cytoskeleton, thereby augmenting the mechanical response of CTLs to their targets. This indicates a potential physical mechanism via which the third signal can enhance the CTL response.
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影响因子：
7
作者：
Curtsinger JM;Mescher MF
通讯作者：
Mescher MF
DOI：
10.1083/jcb.201201018
发表时间：
2012-06-11
期刊：
The Journal of cell biology
影响因子：
--
作者：
Babich A;Li S;O'Connor RS;Milone MC;Freedman BD;Burkhardt JK
通讯作者：
Burkhardt JK
NAADP 激活 T 细胞溶细胞颗粒上的双孔通道，刺激胞吐作用和杀伤作用。
影响因子：
9.2
作者：
Davis, Lianne C.;Morgan, Anthony J.;Chen, Ji-Li;Snead, Charlotte M.;Bloor-Young, Duncan;Shenderov, Eugene;Stanton-Humphreys, Megan N.;Conway, Stuart J.;Churchill, Grant C.;Parrington, John;Cerundolo, Vincenzo;Galione, Antony
通讯作者：
Galione, Antony
影响因子：
7.7
作者：
Blumenthal, Daniel;Chandra, Vidhi;Burkhardt, Janis K.
通讯作者：
Burkhardt, Janis K.
影响因子：
32.4
作者：
Bunnell, SC;Kapoor, V;Samelson, LE
通讯作者：
Samelson, LE