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

Paroxysmal nocturnal haemoglobin- uria (PNH) is a haematopoieis disorder character- ized by the expansion of a stem cell bearing a somatic mutation in the phosphatidylinositol gly- can-A (PIG-A) gene, which is involved in the bio- synthesis 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 hypoth- esized. We focused on the analysis of T lympho- cytes 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 prolif- eration, interferon- production, CD25, CD54, and human leukocyte antigen-DR surface expres- sion were observed. By contrast, GPI T lympho- cytes showed a significant increase of all these pa- rameters, and the analysis of CD40-dependent pathways revealed a functional persistence of CD154 expression on the CD48CD4 lympho- cytes. The alterations of the GPI T cell subset could be involved in the biological mechanisms underlying PNH pathogenesis. J. Leukoc. Biol. 78: 000-000; 2005.