Glycosylphosphatidylinositol-specific, CD1d-restricted T cells in paroxysmal nocturnal hemoglobinuria

Lucia Gargiulo, Maria Papaioannou, Michela Sica, Giulia Talini, Aristeidis Chaidos, Barbara Richichi, Andrei V. Nikolaev, Cristina Nativi, Mark Layton, Josu de la Fuente, Irene Roberts, Lucio Luzzatto, Rosario Notaro, Anastasios Karadimitris

    Research output: Contribution to journalArticlepeer-review

    80 Citations (Scopus)

    Abstract

    The mechanism of bone marrow failure (BMF) in paroxysmal nocturnal hemoglobinuria (PNH) is not yet known. Because in PNH the biosynthesis of the glycolipid molecule glycosylphosphatidylinositol (GPI) is disrupted in hematopoietic stem and progenitor cells by a somatic mutation in the PIG-A gene, BMF might result from an autoimmune attack, whereby T cells target GPI in normal cells, whereas PIG-A mutant GPI-negative cells are spared. In a deliberate test of this hypothesis, we have demonstrated in PNH patients the presence of CD8(+) T cells reactive against antigen-presenting cells (APCs) loaded with GPI. These T cells were significantly more abundant in PNH patients than in healthy controls; their reactivity depended on CD1d expression and they increased upon coculture with CD1d-expressing, GPI-positive APCs. In GPI-specific T cells captured by CD1d dimer technology, we identified, through global T-cell receptor alpha (TCR alpha) analysis, an invariant TCRV alpha 21 sequence, which was then found at frequencies higher than background in the TCR repertoire of 6 of 11 PNH patients. Thus, a novel, autoreactive, CD1d-restricted, GPI-specific T-cell population, enriched in an invariant TCR alpha chain, is expanded in PNH patients and may be responsible for BMF in PNH. (Blood. 2013;121(14):2753-2761)

    Original languageEnglish
    Pages (from-to)2753-2761
    Number of pages9
    JournalBlood
    Volume121
    Issue number14
    DOIs
    Publication statusPublished - 4 Apr 2013

    Keywords

    • LYMPHOCYTES
    • NKT CELLS
    • SOMATIC MUTATIONS
    • HEMATOPOIETIC STEM
    • RECEPTOR
    • TRYPANOSOMA-CRUZI
    • EXPRESSION
    • PATHOGENESIS
    • CD1D
    • APLASTIC-ANEMIA

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