Laboratory of Molecular Cell Biology, Centre for DNA Fingerprinting and Diagnostics (CDFD), Hyderabad, India.
Graduate Studies, Manipal Academy of Higher Education, Manipal, India.
Eur J Immunol. 2021 Mar;51(3):603-619. doi: 10.1002/eji.201848071. Epub 2020 Dec 1.
PPE18 protein belongs to PE/PPE family of Mycobacterium tuberculosis. We reported earlier that PPE18 protein provides survival advantage to M. tuberculosis during infection. In the current study, we found that PPE18 inhibits MHC class II-mediated antigen presentation by macrophages in a dose-dependent manner without affecting the surface level of MHC class II or co-stimulatory molecules. PPE18 does not affect antigen uptake or presentation of preprocessed peptide by macrophages. Antigen degradation was found to be inhibited by PPE18 protein due to perturbation in phagolysosomal acidification. PPE18-mediated inhibition of MHC class II antigen presentation caused poorer activation of CD4 T cells. Mice infected with M. smegmatis expressing PPE18 exhibited reduced maturation and activation of B cells and had decreased Mycobacteria-specific antibody titers. Thus M. tuberculosis probably utilizes PPE18 to inhibit MHC class II antigen presentation causing poorer activation of adaptive immune responses. This study may be useful in understanding host-pathogen interaction and open up directions of designing novel therapeutics targeting PPE18 to tackle this nefarious pathogen.
PPE18 蛋白属于结核分枝杆菌的 PE/PPE 家族。我们之前曾报道过，PPE18 蛋白在感染期间为结核分枝杆菌提供生存优势。在本研究中，我们发现 PPE18 以剂量依赖的方式抑制巨噬细胞中 MHC Ⅱ类介导的抗原呈递，而不影响 MHC Ⅱ类或共刺激分子的表面水平。PPE18 不影响抗原摄取或巨噬细胞预处理肽的呈递。由于吞噬体酸化受到干扰，发现抗原降解被 PPE18 蛋白抑制。PPE18 介导的 MHC Ⅱ类抗原呈递抑制导致 CD4 T 细胞的激活较差。感染表达 PPE18 的耻垢分枝杆菌的小鼠表现出 B 细胞成熟和激活减少，并且针对分枝杆菌特异性抗体滴度降低。因此，结核分枝杆菌可能利用 PPE18 抑制 MHC Ⅱ类抗原呈递，从而导致适应性免疫反应的激活较差。这项研究可能有助于理解宿主-病原体相互作用，并为设计针对 PPE18 的新型治疗方法以应对这种有害病原体开辟方向。
