Article

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

Centre for Haematology, Department of Medicine, Hammersmith Hospital, Imperial College London, London, United Kingdom
Blood (Impact Factor: 10.43). 01/2013; 121(14). DOI: 10.1182/blood-2012-11-469353
Source: PubMed

ABSTRACT The mechanism of bone marrow failure (BMF) in paroxysmal nocturnal hemoglobinuria (PNH) is not yet known. Since 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 auto-immune 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 (APC) 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 co-culture with CD1d-expressing, GPI-positive APC. In GPI-specific T-cells captured by CD1d dimer technology, we identified, through global T-cell receptor alpha (TCRα) analysis, an invariant TCRVα21 sequence, which was then found at frequencies higher than background in the TCR repertoire of 6 out of 11 PNH patients. Thus, a novel, autoreactive, CD1d-restricted, GPI-specific T-cell population, enriched in an invariant TCRα chain, is expanded in PNH patients and may be responsible for BMF in PNH.

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