T cells from paroxysmal nocturnal haemoglobinuria (PNH) patients show an altered CD40-dependent pathway

Paroxysmal nocturnal haemoglobinuria (PNH) is a haematopoiesis disorder characterized by the expansion of a stem cell bearing a somatic mutation in the phosphatidylinositol glycan-A (PIG-A) gene, which is involved in the biosynthesis of the glycosylphosphatidylinositol (GPI) anchor. A number of data suggest the inability of the PIG-A mutation to account alone for the clonal dominance of the GPI-defective clone and for the development of PNH. In this context, additional immune-mediated mechanisms have been hypothesized. We focused on the analysis of T lymphocytes in three PNH patients bearing a mixed GPI and GPI^- T cell population and showing a marked cytopenia. To analyze the biological mechanisms underlying the control of T cell homeostasis in PNH, we addressed the study of CD40-dependent pathways, suggested to be of crucial relevance for the control of autoreactive T cell clones. Our data revealed significant, functional alterations in GPI⁺ and GPI ^- T cell compartments. In the GPI^- T cells, severe defects in T cell receptor-dependent proliferation, interferon-γ production, CD25, CD54, and human leukocyte antigen-DR surface expression were observed. By contrast, GPI⁺ T lymphocytes showed a significant increase of all these parameters, and the analysis of CD40-dependeiit pathways revealed a functional persistence of CD154 expression on the CD48⁺CD4 ⁺ lymphocytes. The alterations of the GPI⁺ T cell subset could be involved in the biological mechanisms underlying PNH pathogenesis.