Abstract
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 in vitro 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.
Highlights
The phosphoinositide 3-kinase–AKT (PI3K–AKT) signaling pathway is involved in many crucial cellular processes including regulation of metabolism, proliferation, apoptosis, cell cycle regulation, and protein synthesis [1,2,3]
Our findings suggest that CD8+ T cells in APDS patients undergo exhaustion, and that this may contribute to the impaired control of persistent viral infections such as Epstein–Barr virus (EBV) and CMV
We found that the frequency of CD160+, CD244+, programmed death receptor (PD)-1+, and CD160+CD244+PD-1+CD8+ T cells is highest in the EBV+ APDS patients (CD160+CD8+: 57 ± 4.9%; CD244+CD8+: 87 ± 3.4%; PD-1+CD8+: 61 ± 8.2%; CD160+CD244+PD-1+CD8+: 36 ± 5.6%), but lower in the EBV− APDS patients and the EBV+ healthy controls (CD160+CD8+: 26 ± 3.8 and 22 ± 4.7%; CD244+CD8+: 43 ± 5.3 and 48 ± 5.9%; PD-1+CD8+: 18 ± 3.0 and 25 ± 7.6%; CD160+CD244+PD1+CD8+: 5.6 ± 1.5 and 7.0 ± 2.5% for EBV− APDS patients and EBV+ healthy control, respectively)
Summary
The phosphoinositide 3-kinase–AKT (PI3K–AKT) signaling pathway is involved in many crucial cellular processes including regulation of metabolism, proliferation, apoptosis, cell cycle regulation, and protein synthesis [1,2,3]. These patients suffer from a specific form of primary immune deficiency called activated PI3Kδ syndrome (APDS) [13, 14] This disease is characterized by disturbed humoral immunity resulting in hypogammaglobulinemia, recurrent respiratory tract infections an absent response to polysaccharide vaccination, pulmonary damage, lymphadenopathy, hepatosplenomegaly, an increased risk for hematological malignancies, and an inability to control persistent viral infections such as Epstein–Barr virus (EBV) and cytomegalovirus (CMV) infections [13, 14]. These patients have decreased numbers of total CD4+ and especially naive CD4+ T cells together with increased CD8+ effector T cells. Several studies indicated that the effector function of their T cells is defective, causing an inability to control chronic viral infections including CMV and EBV infections [13, 14]
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