Abstract
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.
Highlights
The human immune system strives to maintain the delicate balance between preventing host susceptibility to various pathogens and limiting immunopathology due to an exacerbated immune response to infections
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
LL patients have poor cell mediated response against M. leprae leading to delayed clearance of the bacilli
Summary
The human immune system strives to maintain the delicate balance between preventing host susceptibility to various pathogens and limiting immunopathology due to an exacerbated immune response to infections. Studies clearly demonstrated the suppressive ability of this sub-population contributing to the reacceptance of suppressor T-cell as a different T-cell lineage [3,4] Characterization of this T-cell sub-population has continued and currently the thymus-derived Treg cells (tTreg cells) and peripherally derived Treg cells (pTreg cells) [5] are the two widely accepted categories of Treg cells [1,6,7]. Both T-cell subtypes play a role in limiting immune reactions in autoimmune diseases and chronic infections [8,9,10,11]. CD39+ Treg cells have been reported as a subset of the CD4+ CD25highFoxP3+ Treg cells in association with chronic infections like tuberculosis (TB) [12], hepatitis B (HBV) and in graft rejections [13,14] and the ability of CD8+ CD39+ Treg cells to suppress antigen specific CD4+ proliferation clearly demonstrated the importance of this subpopulation [15]
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