Mycobacterium leprae-Specific, HLA Class II-Restricted Killing of Human Schwann Cells by CD4+ Th1 Cells: A Novel Immunopathogenic Mechanism of Nerve Damage in Leprosy

Eric Spierings, Tjitske de Boer, Brigitte Wieles, Linda B. Adams, Enrico Marani, Tom H.M. Ottenhof

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    Abstract

    Peripheral nerve damage is a major complication of reversal (or type-1) reactions in leprosy. The pathogenesis of nerve damage remains largely unresolved, but detailed in situ analyses suggest that type-1 T cells play an important role. Mycobacterium leprae is known to have a remarkable tropism for Schwann cells of the peripheral nerve. Reversal reactions in leprosy are often accompanied by severe and irreversible nerve destruction and are associated with increased cellular immune reactivity against M. leprae. Thus, a likely immunopathogenic mechanism of Schwann cell and nerve damage in leprosy is that infected Schwann cells process and present Ags of M. leprae to Ag-specific, inflammatory type-1 T cells and that these T cells subsequently damage and lyse infected Schwann cells. Thus far it has been difficult to study this directly because of the inability to grow large numbers of human Schwann cells. We now have established long-term human Schwann cell cultures from sural nerves and show that human Schwann cells express MHC class I and II, ICAM-1, and CD80 surface molecules involved in Ag presentation. Human Schwann cells process and present M. leprae, as well as recombinant proteins and peptides to MHC class II-restricted CD4+ T cells, and are efficiently killed by these activated T cells. These findings elucidate a novel mechanism that is likely involved in the immunopathogenesis of nerve damage in leprosy.

    Acute reactional episodes are major complications in leprosy. Type-1 reversal reactions (RR)3 in particular can result in irreversible tissue damage and nerve destruction. Such reactions are characterized by strongly increased cellular immune responses in peripheral blood and lesions (1) accompanied by the abundant presence of local CD4+ T cells (1, 2, 3) and type-1 cytokines (2, 4, 5, 6). In tuberculoid and RR granulomas, cells that express serine esterase, a component of cytotoxic granules, colocalize with CD4+ CD45RO+ memory T cells (2), and analysis of Mycobacterium leprae-reactive T cells confirmed that these T cells indeed produce serine esterase in vitro (7). The induction of cytolytic CD4+ Th1-like cells during mycobacterial infections has been documented extensively (7, 8, 9, 10), further suggesting that cytotoxic Th1 cells may play a major role in the protection against and the immunopathology of mycobacterial infections. However, direct evidence for a pathogenic role of T cells in Schwann cell damage is lacking. Better insight into the immunopathogenesis of Schwann cell damage in leprosy is required, given the major impact of nerve damage in leprosy.

    M. leprae has a remarkable affinity for Schwann cells, the molecular basis of which has been elucidated recently: M. leprae binds specifically to the G domain of the extracellular matrix protein laminin-2, which ligates to α/β-dystroglycan receptor-complexes on myelinating Schwann cells (11, 12, 13). Thus, M. leprae exploits interactions between matrix- and cytoskeletal-linked glycoproteins to target and infect Schwann cells. The recent elucidation of this mechanism now provides novel opportunities to disrupt interactions between M. leprae, Schwann cells, and inflammatory T cells and is of potential value in the prevention or treatment of nerve damage.

    Previously, Steinhoff et al. showed in a mouse model that Schwann cells can be lysed by CD8+ T cells in an Ag-specific manner (14), suggesting that murine Schwann cells are susceptible to killing by CD8+ T cells. However, CD4+ T cells, which form the major cellular component of granulomatous leprosy lesions, were not examined.

    We now have established human Schwann cell cultures and analyzed their Ag-presenting capacity and their susceptibility to killing by M. leprae-reactive T cells in a human setting. Our data show that human Schwann cells process and present M. leprae to Ag-specific T cells and are subsequently killed during this event. We propose that this could be an important mechanism in nerve damage.
    Original languageEnglish
    Pages (from-to)5883-5888
    JournalJournal of immunology
    Volume166
    Issue number10
    DOIs
    Publication statusPublished - 2001

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