Exhaustion of the CD8+ T cell compartment in patients with mutations in phosphoinositide 3-kinase delta
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.
|Keywords||Activated phosphoinositide 3-kinase delta syndrome, CD8+ T cells, Checkpoint inhibition, Exhaustion, P110δ, PI3K, Programmed death receptor-1|
|Persistent URL||dx.doi.org/10.3389/fimmu.2018.00446, hdl.handle.net/1765/105133|
|Journal||Frontiers in Immunology|
Wentink, M.W.J, Mueller, Y.M, Dalm, V.A.S.H, Driessen, G.J.A, van Hagen, P.M, van Montfrans, J.M, … Katsikis, P.D. (2018). Exhaustion of the CD8+ T cell compartment in patients with mutations in phosphoinositide 3-kinase delta. Frontiers in Immunology, 9(MAR). doi:10.3389/fimmu.2018.00446