Details

Autor(en) / Beteiligte

• Wentink, Marjolein W J
• Mueller, Yvonne M
• Dalm, Virgil A S H
• Driessen, Gertjan J
• van Hagen, P Martin
• van Montfrans, Joris M
• van der Burg, Mirjam
• Katsikis, Peter D

Titel

Exhaustion of the CD8 + T Cell Compartment in Patients with Mutations in Phosphoinositide 3-Kinase Delta

Ist Teil von

• Frontiers in immunology, 2018-03, Vol.9, p.446-446

Ort / Verlag

Switzerland: Frontiers Research Foundation

Erscheinungsjahr

2018

Link zum Volltext

Quelle

EZB Electronic Journals Library

Beschreibungen/Notizen

• Pathogenic gain-of-function mutations in the gene encoding phosphoinositide 3-kinase delta (PI3Kδ) cause activated PI3Kδ syndrome (APDS), a disease characterized by humoral immunodeficiency, lymphadenopathy, and an inability to control persistent viral infections including Epstein-Barr virus (EBV) and cytomegalovirus (CMV) infections. Understanding the mechanisms leading to impaired immune response is important to optimally treat APDS patients. Immunosenescence of CD8 T cells was suggested to contribute to APDS pathogenesis. However, the constitutive activation of T cells in APDS may also result in T cell exhaustion. Therefore, we studied exhaustion of the CD8 T cell compartment in APDS patients and compared them with healthy controls and HIV patients, as a control for exhaustion. The subset distribution of the T cell compartment of APDS patients was comparable with HIV patients with decreased naive CD4 and CD8 T cells and increased effector CD8 T cells. Like in HIV patients, expression of activation markers and inhibitory receptors CD160, CD244, and programmed death receptor (PD)-1 on CD8 T cells was increased in APDS patients, indicating exhaustion. EBV-specific CD8 T cells from APDS patients exhibited an exhausted phenotype that resembled HIV-specific CD8 T cells in terms of inhibitory receptor expression. Inhibition of PD-1 on EBV-specific CD8 T cells from APDS patients enhanced proliferation and effector cytokine production. Based on these results, we conclude that total and EBV-specific CD8 T cells from APDS patients are characterized by T cell exhaustion. Furthermore, PD-1 checkpoint inhibition may provide a possible therapeutic approach to support the immune system of APDS patients to control EBV and CMV.