DST-NRF Centre of Excellence for Biomedical Tuberculosis Research, South African Medical Research Council Centre for Tuberculosis Research, Division of Molecular Biology and Human Genetics, Faculty of Medical and Health Sciences, Stellenbosch University, Cape Town, South Africa.
Institute of Immunology, Friedrich-Loeffler-Institut, Greifswald-Insel Riems, Germany; Faculty of Mathematics and Natural Sciences, University of Greifswald, Greifswald, Germany.
Cell Immunol. 2021 Jun;364:104359. doi: 10.1016/j.cellimm.2021.104359. Epub 2021 Apr 8.
Conventional anti-tuberculosis (TB) therapies comprise lengthy antibiotic treatment regimens, exacerbated by multi-drug resistant and extensively drug resistant mycobacterial strains. We assessed the ability of all-trans retinoic acid (ATRA), as repurposed compound serving as host-directed therapy (HDT), to counteract the suppressive effects of myeloid-derived suppressor cells (MDSCs) obtained from active TB cases (untreated or during week one of treatment) on T-cell responsiveness. We show for the first time that MDSCs suppress non-specific T-cell activation and production of interleukin (IL)-2, IL-4, IL-13 and GM-CSF via contact-dependent mechanisms. ATRA treatment decreases MDSC frequency, but fails to mature MDSCs to non-suppressive, terminally differentiated myeloid cells and does not restore T-cell function or cytokine production in the presence of MDSCs. The impact of ATRA treatment on improved immunity, using the concentration tested here, is likely to be minimal, but further identification and development of MDSC-targeting TB host-directed therapies are warranted.
常规的抗结核（TB）治疗包括长期的抗生素治疗方案，但由于耐多药和广泛耐药的分枝杆菌菌株，情况变得更加复杂。我们评估了全反式维甲酸（ATRA）作为重新利用的化合物作为宿主定向治疗（HDT）的能力，以对抗从活动性 TB 病例（未经治疗或在治疗的第一周）获得的髓源性抑制细胞（MDSC）对 T 细胞反应性的抑制作用。我们首次表明，MDSC 通过接触依赖性机制抑制非特异性 T 细胞激活和白细胞介素（IL）-2、IL-4、IL-13 和 GM-CSF 的产生。ATRA 治疗可降低 MDSC 的频率，但不能使 MDSC 成熟为非抑制性、终末分化的髓样细胞，并且在 MDSC 存在的情况下不能恢复 T 细胞功能或细胞因子的产生。在测试的浓度下，ATRA 治疗对改善免疫的影响可能很小，但进一步鉴定和开发针对 MDSC 的 TB 宿主定向治疗是必要的。
