A CD4+CD161+ T-Cell Subset Present in Unexposed Humans, Not Tb Patients, Are Fast Acting Cells That Inhibit the Growth of Intracellular Mycobacteria Involving CD161 Pathway, Perforin, and IFN-γ/Autophagy.
A CD4+CD161+ T-Cell Subset Present in Unexposed Humans, Not Tb Patients, Are Fast Acting Cells That Inhibit the Growth of Intracellular Mycobacteria Involving CD161 Pathway, Perforin, and IFN-γ/Autophagy.
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存在于未暴露人群（而非结核病患者）中的 CD4 CD161 T 细胞亚群是快速作用的细胞，可抑制涉及 CD161 途径、穿孔素和 IFN-γ/自噬的细胞内分枝杆菌的生长
DOI：
10.3389/fimmu.2021.599641
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发表时间：
2021
影响因子：
7.3
通讯作者：
Chen ZW
中科院分区：
文献类型：
--
作者：
Yang R;Peng Y;Pi J;Liu Y;Yang E;Shen X;Yao L;Shen L;Modlin RL;Shen H;Sha W;Chen ZW
目前尚不清楚CD4+T细胞亚群是否可以作为快速反应细胞来控制结核分枝杆菌(Mtb)感染。在这里，我们表明，在未暴露的健康人中，原始的CD4+CD161+T细胞亚群，而不是CD4+CD161-，在接触受感染的自体和异体巨噬细胞或肺上皮A549细胞时，快速发挥非传统T细胞的作用，能够抑制细胞内Mtb和BCG的生长。这种抑制与原代CD_4+CD_(161)+T细胞在结核分枝杆菌作用下快速表达/分泌抗结核细胞因子的能力相一致，包括干扰素-γ、肿瘤坏死因子-α、白介素17和穿孔素。通过阻断单抗阻断CD16 1途径、穿孔素或干扰素-γ，从机制上削弱了CD16 1+T细胞抑制细胞内分枝杆菌生长的能力。用自噬抑制剂对感染的巨噬细胞进行预处理也可阻断CD4+CD161+T细胞对分枝杆菌的生长抑制。过继转移人CD4+CD161+T细胞对SCID小鼠具有抗分枝杆菌感染的保护性免疫作用。令人惊讶的是，结核病患者的CD_4+CD_(161+)T细胞表现出产生穿孔素/干扰素-γ的能力丧失或降低，并抑制感染巨噬细胞中分枝杆菌的细胞内生长。这些免疫功能紊乱与PD1/TIM3上调活动性肺结核患者外周血中CD4+CD161+T细胞的表达一致，PD1/TIM3对这一亚群细胞的阻断增强了对细胞内分枝杆菌存活的抑制作用。因此，这些发现表明，在未暴露的人中，快速作用的初级CD_4+CD_(161+)T细胞亚群利用CD_(161)途径、穿孔素和干扰素-γ/自噬来抑制细胞内分枝杆菌的生长，从而将它们与传统CD_4+T细胞的缓慢适应反应区分开来。快速作用的CD4+CD161+T细胞的存在抑制了未接触结核杆菌的人的分枝杆菌生长，但在结核病患者中不存在，这也暗示了这些细胞在针对初始结核分枝杆菌感染的保护性免疫中的作用。
It remains undefined whether a subset of CD4+ T cells can function as fast-acting cells to control Mycobacterium tuberculosis (Mtb) infection. Here we show that the primary CD4+CD161+ T-cell subset, not CD4+CD161-, in unexposed healthy humans fast acted as unconventional T cells capable of inhibiting intracellular Mtb and BCG growth upon exposure to infected autologous and allogeneic macrophages or lung epithelial A549 cells. Such inhibition coincided with the ability of primary CD4+CD161+ T cells to rapidly express/secrete anti-TB cytokines including IFN-γ, TNF-α, IL-17, and perforin upon exposure to Mtb. Mechanistically, blockades of CD161 pathway, perforin or IFN-γ by blocking mAbs abrogated the ability of CD4+CD161+ T cells to inhibit intracellular mycobacterial growth. Pre-treatment of infected macrophages with inhibitors of autophagy also blocked the CD4+CD161+ T cell-mediated growth inhibition of mycobacteria. Furthermore, adoptive transfer of human CD4+CD161+ T cells conferred protective immunity against mycobacterial infection in SCID mice. Surprisingly, CD4+CD161+ T cells in TB patients exhibited a loss or reduction of their capabilities to produce perforin/IFN-γ and to inhibit intracellular growth of mycobacteria in infected macrophages. These immune dysfunctions were consistent with PD1/Tim3 up-regulation on CD4+CD161+ T cells in active tuberculosis patients, and the blockade of PD1/Tim3 on this subset cells enhanced the inhibition of intracellular mycobacteria survival. Thus, these findings suggest that a fast-acting primary CD4+CD161+T-cell subset in unexposed humans employs the CD161 pathway, perforin, and IFN-γ/autophagy to inhibit the growth of intracellular mycobacteria, thereby distinguishing them from the slow adaptive responses of conventional CD4+ T cells. The presence of fast-acting CD4+CD161+ T-cell that inhibit mycobacterial growth in unexposed humans but not TB patients also implicates the role of these cells in protective immunity against initial Mtb infection.
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影响因子：
3.7
作者：
Gao L;Zhou F;Li X;Jin Q
通讯作者：
Jin Q
影响因子：
17.1
作者：
Fabri M;Stenger S;Shin DM;Yuk JM;Liu PT;Realegeno S;Lee HM;Krutzik SR;Schenk M;Sieling PA;Teles R;Montoya D;Iyer SS;Bruns H;Lewinsohn DM;Hollis BW;Hewison M;Adams JS;Steinmeyer A;Zügel U;Cheng G;Jo EK;Bloom BR;Modlin RL
通讯作者：
Modlin RL
人白细胞介素17产生的细胞起源于CD161+ CD4+ T细胞前体。
影响因子：
15.3
作者：
Cosmi, Lorenzo;De Palma, Raffaele;Santarlasci, Veronica;Maggi, Laura;Capone, Manuela;Frosali, Francesca;Rodolico, Gabriella;Querci, Valentina;Abbate, Gianfranco;Angeli, Roberta;Berrino, Liberato;Fambrini, Massimiliano;Caproni, Marzia;Tonelli, Francesco;Lazzeri, Elena;Parronchi, Paola;Liotta, Francesco;Maggi, Enrico;Romagnani, Sergio;Annunziato, Francesco
通讯作者：
Annunziato, Francesco
影响因子：
82.9
作者：
Dijkman, Karin;Sombroek, Claudia C.;Verreck, Frank A. W.
通讯作者：
Verreck, Frank A. W.
影响因子：
4.4
作者：
Aldemir, H;Prod'homme, V;Braud, VM
通讯作者：
Braud, VM