T-Cell Regulation in Lepromatous Leprosy

Kidist Bobosha, Louis Wilson, Krista E. van Meijgaarden, Yonas Bekele, Martha Zewdie, Jolien J. van der Ploeg-van Schip, Markos Abebe, Jemal Hussein, Saraswoti Khadge, Kapil D. Neupane, Deanna A. Hagge, Ekaterina S. Jordanova, Abraham Aseffa, Tom H. M. Ottenhoff, Annemieke Geluk

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Author Summary Leprosy is a curable infectious disease caused by Mycobacterium leprae (M. leprae) that affects the skin and peripheral nerves. It is manifested in different forms ranging from self-healing, tuberculoid leprosy (TT) with low bacillary load and high cellular immunity against M. leprae, to lepromatous leprosy (LL) with high bacillary load and high antibody titers to M. leprae antigens. However, LL patients have poor cell mediated response against M. leprae leading to delayed clearance of the bacilli. A possible explanation for this bacterial persistence could lie in the presence of more regulatory cells at infection sites and in peripheral blood. This study shows the recovery of the cell mediated response by depletion of CD25(+) cells in a subset of LL patients, while another patient subset was not affected similarly. Moreover, an increased frequency of FoxP3(+) T cells together with anti-inflammatory macrophages was observed in LL patients' skin biopsies. Thus, these data show that CD25(+) T-reg cells play a role in M. leprae-unresponsiveness in leprosy patients. Regulatory T (T-reg) 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-gamma 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-gamma 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-gamma 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(+) T-reg cells play a role in M. leprae-Th1 unresponsiveness in LL
Original languageEnglish
Article numbere2773
Pages (from-to)e2773
JournalPLoS Neglected Tropical Diseases
Issue number4
Publication statusPublished - 2014

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