TY - JOUR
T1 - Patients with paroxysmal nocturnal hemoglobinuria have a high frequency of peripheral-blood T cells expressing activating isoforms of inhibiting superfamily receptors
AU - Poggi, Alessandro
AU - Negrini, Simone
AU - Zocchi, Maria Raffaella
AU - Massaro, Anna Maria
AU - Garbarino, Lucia
AU - Lastraioli, Sonia
AU - Gargiulo, Lucia
AU - Luzzatto, Lucio
AU - Notaro, Rosario
PY - 2005/10
Y1 - 2005/10
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=27144506207&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=27144506207&partnerID=8YFLogxK
U2 - 10.1182/blood-2004-11-4315
DO - 10.1182/blood-2004-11-4315
M3 - Article
C2 - 15956278
AN - SCOPUS:27144506207
VL - 106
SP - 2399
EP - 2408
JO - Blood
JF - Blood
SN - 0006-4971
IS - 7
ER -