T-Cell Regulation in Lepromatous Leprosy

Regulatory T (Treg) cells are known for their role in maintaining self-tolerance and balancing immune reactions in autoimmune diseases and chronic infections. However, regulatory mechanisms can also lead to prolonged survival of pathogens in chronic infections like leprosy and tuberculosis (TB). Despite high humoral responses against Mycobacterium leprae (M. leprae), lepromatous leprosy (LL) patients have the characteristic inability to generate T helper 1 (Th1) responses against the bacterium. In this study, we investigated the unresponsiveness to M. leprae in peripheral blood mononuclear cells (PBMC) of LL patients by analysis of IFN-γ responses to M. leprae before and after depletion of CD25+ cells, by cell subsets analysis of PBMC and by immunohistochemistry of patients' skin lesions. Depletion of CD25+ cells from total PBMC identified two groups of LL patients: 7/18 (38.8%) gained in vitro responsiveness towards M. leprae after depletion of CD25+ cells, which was reversed to M. leprae-specific T-cell unresponsiveness by addition of autologous CD25+ cells. In contrast, 11/18 (61.1%) remained anergic in the absence of CD25+ T-cells. For both groups mitogen-induced IFN-γ was, however, not affected by depletion of CD25+ cells. In M. leprae responding healthy controls, treated lepromatous leprosy (LL) and borderline tuberculoid leprosy (BT) patients, depletion of CD25+ cells only slightly increased the IFN-γ response. Furthermore, cell subset analysis showed significantly higher (p = 0.02) numbers of FoxP3+ CD8+CD25+ T-cells in LL compared to BT patients, whereas confocal microscopy of skin biopsies revealed increased numbers of CD68+CD163+ as well as FoxP3+ cells in lesions of LL compared to tuberculoid and borderline tuberculoid leprosy (TT/BT) lesions. Thus, these data show that CD25+ Treg cells play a role in M. leprae-Th1 unresponsiveness in LL.

调节性T（Regulatory T, Treg）细胞以维持自身耐受、平衡自身免疫病与慢性感染中的免疫反应为核心功能。然而，免疫调节机制也可导致病原体在麻风、结核（TB）等慢性感染中长期存活。尽管针对麻风分枝杆菌（Mycobacterium leprae, M. leprae）的体液免疫应答水平较高，但瘤型麻风（lepromatous leprosy, LL）患者的典型特征是无法产生针对该菌的T辅助细胞1（T helper 1, Th1）应答。本研究通过检测CD25+细胞耗竭前后瘤型麻风患者外周血单个核细胞（peripheral blood mononuclear cells, PBMC）对麻风分枝杆菌的IFN-γ应答、对外周血单个核细胞进行细胞亚群分析，以及对患者皮肤病变组织开展免疫组化检测，探究了瘤型麻风患者外周血单个核细胞对麻风分枝杆菌的无应答状态。对总外周血单个核细胞进行CD25+细胞耗竭后，18例瘤型麻风患者被分为两组：7例（38.8%）在CD25+细胞耗竭后获得了体外针对麻风分枝杆菌的应答能力，而加入自体CD25+细胞后，该应答可被逆转回麻风分枝杆菌特异性T细胞无应答状态；与之相反，11例（61.1%）患者在去除CD25+ T细胞后仍处于免疫无应答状态。不过，两类患者的丝裂原诱导的IFN-γ产生均不受CD25+细胞耗竭的影响。在对麻风分枝杆菌产生应答的健康对照、经治疗的瘤型麻风患者以及界线类偏结核样型麻风（borderline tuberculoid leprosy, BT）患者中，CD25+细胞耗竭仅轻微提升了IFN-γ应答水平。此外，细胞亚群分析显示，瘤型麻风患者的FoxP3+ CD8+CD25+ T细胞数量显著高于BT患者（p=0.02）；而皮肤活检组织的共聚焦显微镜观察发现，与结核样型麻风及界线类偏结核样型麻风病变相比，瘤型麻风病变组织中CD68+CD163+细胞与FoxP3+细胞的数量均有所增加。综上，本研究数据表明，CD25+ Treg细胞参与了瘤型麻风患者体内针对麻风分枝杆菌的Th1应答无应答状态。