Bond Nell G, Fahlberg Marissa D, Yu Shan, Rout Namita, Tran Dollnovan, Fitzpatrick-Schmidt Taylor, Sprehe Lesli M, Scheef Elizabeth A, Mudd Joseph C, Schaub Robert, Kaur Amitinder
Tulane National Primate Research Center, Division of Immunology, Covington, LA 70433, USA.
RGS Consulting, Pelham, NH 03076, USA.
iScience. 2022 Feb 9;25(3):103889. doi: 10.1016/j.isci.2022.103889. eCollection 2022 Mar 18.
Invariant natural killer T-lymphocytes (iNKT) are unique immunomodulatory innate T cells with an invariant TCRα recognizing glycolipids presented on MHC class-I-like CD1d molecules. Activated iNKT rapidly secrete pro-and anti-inflammatory cytokines, potentiate immunity, and modulate inflammation. Here, we report the effects of iNKT activation in Mauritian-origin cynomolgus macaques by a humanized monoclonal antibody, NKTT320, that binds to the invariant region of the iNKT TCR. NKTT320 led to rapid iNKT activation, increased polyfunctionality, and elevation of multiple plasma analytes within 24 hours. Flow cytometry and RNA-Seq confirmed downstream activation of multiple immune subsets, enrichment of JAK/STAT and PI3K/AKT pathway genes, and upregulation of inflammation-modulating genes. NKTT320 also increased iNKT frequency in adipose tissue and did not cause iNKT anergy. Our data indicate that NKTT320 has a sustained effect on iNKT activation, potentiation of innate and adaptive immunity, and resolution of inflammation, which supports its future use as an immunotherapeutic.
不变自然杀伤T淋巴细胞（iNKT）是独特的免疫调节性固有T细胞，其具有识别呈递于MHC I类样CD1d分子上的糖脂的不变TCRα。活化的iNKT迅速分泌促炎和抗炎细胞因子，增强免疫力并调节炎症。在此，我们报告了一种人源化单克隆抗体NKTT320对源自毛里求斯的食蟹猴中iNKT激活的影响，该抗体与iNKT TCR的恒定区结合。NKTT320导致iNKT迅速激活、多功能性增加，并在24小时内使多种血浆分析物水平升高。流式细胞术和RNA测序证实了多个免疫亚群的下游激活、JAK/STAT和PI3K/AKT通路基因的富集以及炎症调节基因的上调。NKTT320还增加了脂肪组织中iNKT的频率，且未导致iNKT无反应性。我们的数据表明，NKTT320对iNKT激活、固有免疫和适应性免疫的增强以及炎症的消退具有持续作用，这支持其未来作为一种免疫疗法的应用。
