Centre for Lung Infection and Immunity, Division of Pulmonology, Department of Medicine and UCT Lung Institute & South African MRC/UCT Centre for the Study of Antimicrobial Resistance, University of Cape Town, Cape Town, South Africa.
DSI-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 Medicine and Health Sciences, Stellenbosch University, Cape Town, South Africa.
Front Immunol. 2021 Jun 1;12:676679. doi: 10.3389/fimmu.2021.676679. eCollection 2021.
Protective host responses in those exposed to or infected with tuberculosis (TB) is thought to require a delicate balance between pro-inflammatory and regulatory immune responses. Myeloid-derived suppressor cells (MDSCs), regulatory cells that dampen T-cell function, have been described in cancer and other infectious diseases but there are limited data on their role in TB.
Peripheral blood was obtained from patients with active pulmonary TB and participants with presumed latent TB infection (LTBI) from Cape Town, South Africa. MDSC frequency was ascertained by flow cytometry. Purified MDSCs were used to assess (i) their suppressive effect on T-cell proliferation using a Ki67 flow cytometric assay and (ii) their effect on mycobacterial containment by co-culturing with H37-infected monocyte-derived macrophages and autologous pre-primed effector T-cells with or without MDSCs. Mycobacterial containment was measured by plating colony forming units (CFU).
MDSCs (CD15HLA-DRCD33) had significantly higher median frequencies (IQR) in patients with active TB (n=10) versus LTBI (n= 10) [8.2% (6.8-10.7) versus 42.2% (27-56) respectively; p=0.001]. Compared to MDSC-depleted peripheral blood mononuclear and effector T cell populations, dilutions of purified MDSCs isolated from active TB patients suppressed T-cell proliferation by up to 72% (n=6; p=0.03) and significantly subverted effector T-cell-mediated containment of H37 in monocyte-derived macrophages (n=7; 0.6% versus 8.5%; p=0.02).
Collectively, these data suggest that circulating MDSCs are induced during active TB disease and can functionally suppress T-cell proliferation and subvert mycobacterial containment. These data may inform the design of vaccines and immunotherapeutic interventions against TB but further studies are required to understand the mechanisms underpinning the effects of MDSCs.
人们认为，接触或感染结核分枝杆菌（TB）的个体中存在保护性宿主反应，需要在促炎和调节性免疫反应之间取得微妙的平衡。髓源抑制细胞（MDSCs）是一种抑制 T 细胞功能的调节细胞，已在癌症和其他传染病中得到描述，但关于其在 TB 中的作用的数据有限。
从南非开普敦的活动性肺结核患者和疑似潜伏性结核感染（LTBI）患者中获得外周血。通过流式细胞术确定 MDSC 的频率。使用纯化的 MDSC 评估（i）Ki67 流式细胞术测定法评估其对 T 细胞增殖的抑制作用，以及（ii）与 H37 感染的单核细胞衍生的巨噬细胞和自体预刺激效应 T 细胞共培养时对分枝杆菌的控制作用。通过平板菌落形成单位（CFU）测定分枝杆菌的控制。
与 LTBI（n=10）相比，活动性 TB 患者（n=10）的 MDSC（CD15HLA-DRCD33）中位数频率（IQR）更高[分别为 8.2%（6.8-10.7）和 42.2%（27-56）；p=0.001]。与 MDSC 耗尽的外周血单核细胞和效应 T 细胞群体相比，从活动性 TB 患者中分离的纯化 MDSC 稀释液可抑制 T 细胞增殖高达 72%（n=6；p=0.03），并显著破坏效应 T 细胞介导的 H37 在单核细胞衍生的巨噬细胞中的控制作用（n=7；0.6%对 8.5%；p=0.02）。
总之，这些数据表明，在活动性 TB 疾病期间，循环 MDSC 被诱导，并可发挥抑制 T 细胞增殖和破坏分枝杆菌控制的功能。这些数据可能为针对 TB 的疫苗和免疫治疗干预措施的设计提供信息，但需要进一步研究以了解 MDSC 作用的机制。
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