PD-1 blockade exacerbates Mycobacterium tuberculosis infection in rhesus macaques.
PD-1 blockade exacerbates Mycobacterium tuberculosis infection in rhesus macaques.
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DOI：
10.1126/sciimmunol.abf3861
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发表时间：
2021-01-15
影响因子：
24.8
通讯作者：
Barber DL
中科院分区：
文献类型：
--
作者：
Kauffman KD;Sakai S;Lora NE;Namasivayam S;Baker PJ;Kamenyeva O;Foreman TW;Nelson CE;Oliveira-de-Souza D;Vinhaes CL;Yaniv Z;Lindestam Arleham CS;Sette A;Freeman GJ;Moore R;NIAID/DIR Tuberculosis Imaging Program;Sher A;Mayer-Barber KD;Andrade BB;Kabat J;Via LE;Barber DL
通过靶向共抑制受体PD-1来增强免疫细胞功能可能在治疗慢性感染中有应用。在这里，我们研究PD-1在结核分枝杆菌（Mtb）感染恒河猴过程中的作用。与同种型对照处理的猴相比，用抗PD-1单克隆抗体处理的动物发展出更差的疾病和更高的肉芽肿细菌载量。PD-1阻断增加了肉芽肿Mtb特异性CD 8 T细胞的数量和功能。相比之下，抗PD-1处理的猕猴中的Mtb特异性CD 4 T细胞在肉芽肿中的数量或功能没有增加，CTLA-4表达水平增加，并且在活体成像研究中表现出病灶内运输减少。在抗PD-1治疗的动物的肉芽肿中，多种促炎细胞因子升高，并且更多的细胞因子与细菌载量相关，从而鉴定了半胱天冬酶1在PD-1阻断后结核病恶化中的作用。最后，发现PD-1阻断后Mtb细菌负荷增加与个体猕猴感染前肠道微生物群的组成相关。因此，需要PD-1介导的共抑制来控制猕猴中的Mtb感染，这可能是由于其在抑制有害炎症以及允许正常的CD 4 T细胞应答中的作用。
Boosting immune cell function by targeting the co-inhibitory receptor PD-1 may have applications in the treatment of chronic infections. Here we examine the role of PD-1 during Mycobacterium tuberculosis (Mtb) infection of rhesus macaques. Animals treated with anti-PD-1 monoclonal antibody developed worse disease and higher granuloma bacterial loads compared to isotype control treated monkeys. PD-1 blockade increased the number and functionality of granuloma Mtb-specific CD8 T cells. In contrast, Mtb-specific CD4 T cells in anti-PD-1 treated macaques were not increased in number or function in granulomas, expressed increased levels of CTLA-4 and exhibited reduced intralesional trafficking in live imaging studies. In granulomas of anti-PD-1 treated animals, multiple proinflammatory cytokines were elevated, and more cytokines correlated with bacterial loads, leading to the identification of a role for caspase 1 in the exacerbation of tuberculosis after PD-1 blockade. Lastly, increased Mtb bacterial loads after PD-1 blockade were found to associate with the composition of the intestinal microbiota prior to infection in individual macaques. Therefore, PD-1-mediated co-inhibition is required for control of Mtb infection in macaques, perhaps due to its role in dampening detrimental inflammation as well as allowing for normal CD4 T cell responses.
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影响因子：
32.4
作者：
Honda T;Egen JG;Lämmermann T;Kastenmüller W;Torabi-Parizi P;Germain RN
通讯作者：
Germain RN
影响因子：
6.7
作者：
Lindestam Arlehamn CS;McKinney DM;Carpenter C;Paul S;Rozot V;Makgotlho E;Gregg Y;van Rooyen M;Ernst JD;Hatherill M;Hanekom WA;Peters B;Scriba TJ;Sette A
通讯作者：
Sette A
DOI：
10.1007/978-1-62703-523-1_9
发表时间：
2013-01-01
期刊：
Methods in molecular biology (Clifton, N.J.)
影响因子：
--
作者：
Jakobs, Christopher;Bartok, Eva;Hornung, Veit
通讯作者：
Hornung, Veit
DOI：
10.1126/science.aao3290
发表时间：
2018-01-05
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Matson V;Fessler J;Bao R;Chongsuwat T;Zha Y;Alegre ML;Luke JJ;Gajewski TF
通讯作者：
Gajewski TF
DOI：
10.1038/nrd.2017.162
发表时间：
2018-01
期刊：
Nature reviews. Drug discovery
影响因子：
--
作者：
Kaufmann SHE;Dorhoi A;Hotchkiss RS;Bartenschlager R
通讯作者：
Bartenschlager R