Patients with paroxysmal nocturnal hemoglobinuria have a high frequency of peripheral-blood T cells expressing activating isoforms of inhibiting superfamily receptors

Patients with paroxysmal nocturnal hemoglobinuria (PNH) have a large clonal population of blood cells deriving from hematopoietic stem cells (HSCs) deficient in glycosylphosphatidylinositol (GPI)-anchored surface molecules. A current model postulates that PNH arises through negative selection against normal HSCs exerted by autoreactive T cells, whereas PNH HSCs escape damage. We have investigated the inhibitory receptor superfamily (IRS) system in 13 patients with PNH. We found a slight increase in the proportion of T cells expressing IRS. In contrast to what applies to healthy donors, the engagement of IRS molecules on T cells from patients with PNH elicited a powerful cytolytic activity in a redirected killing assay, indicating that these IRSs belong to the activating type. This was confirmed by clonal analysis: 50% of IRS⁺ T-cell clones in patients with PNH were of the activating type, while only 5% were of the activating type in healthy donors. Moreover, the ligation of IRS induces (1) production of tumor necrosis factor α (TNF-α) and interferon γ (IFN-γ) and (2) brisk cytolytic activity against cells bearing appropriate IRS counterligands. In addition, these IRS⁺ T cells show natural killer (NK)-like cytolytic activity to which GPI^- cells were less sensitive than GPI⁺ cells. Thus, T cells with NK-like features, expressing the activating isoforms of IRS, may include effector cells involved in the pathogenesis of PNH.