Genetic Defects in Phosphoinositide 3-Kinase δ Influence CD8+ T Cell Survival, Differentiation, and Function

Abstract

Activated phosphoinositide 3-kinase delta syndrome (APDS), also known as p110 delta-activating mutation causing senescent T cells, lymphadenopathy and immunodeficiency (PASLI), is an autosomal dominant primary human immunodeficiency (PID) caused by heterozygous gain-of-function mutations in PIK3CD, which encodes the p110δ catalytic subunit of PI3K. This recently described PID is characterized by diverse and heterogeneous clinical manifestations that include recurrent respiratory infections, lymphoproliferation, progressive lymphopenia, and defective antibody responses. A major clinical manifestation observed in the NIH cohort of patients with PIK3CD mutations is chronic Epstein-Barr virus (EBV) and/or cytomegalovirus viremia. Despite uncontrolled EBV infection, many APDS/PASLI patients had normal or higher frequencies of EBV-specific CD8⁺ T cells. In this review, we discuss data pertaining to CD8⁺ T cell function in APDS/PASLI, including increased cell death, expression of exhaustion markers, and altered killing of autologous EBV-infected B cells, and how these and other data on PI3K provide insight into potential cellular defects that prevent clearance of chronic infections.

Keywords: Epstein–Barr virus; activated phosphoinositide 3-kinase delta syndrome; cytotoxic T lymphocyte; lymphadenopathy and immunodeficiency; p110δ activating mutation causing senescent T cells; primary human immunodeficiency.

Figure 1

Defects in CD8⁺ T cells may contribute to impaired clearance of Epstein–Barr virus and CMV in activated phosphoinositide 3-kinase delta syndrome/PASLI. These include: (1) decreased naïve T cells; (2) increased T cell receptor-stimulated cell death; (3) altered differentiation with increased effector cell function at the expense of memory cell formation; and (4) expression of inhibitory receptors associated with exhaustion and/or senescence. These defects are associated with altered signaling (pAKT and mTOR) that, in turn, could affect the activation and/or expression of transcription factors (FOXO1, TCF1, and BACH2).

Figure 2

Patient CD8⁺ T cells display elevated expression of inhibitory receptors and impaired killing of autologous targets. (A) Elevated expression of inhibitory receptors PD-1 and 2B4, and senescence marker CD57 on allo-reactive CD8⁺ T cells. Expression of the signaling lymphocyte activation molecule family receptor, NTB-A, remained unchanged, while SAP expression can be reduced. Representative example shown [3 healthy donor (HD) controls, 3–5 patients] [PT], small horizon line represents mean, *p < 0.05 (Mann–Whitney test). (B) Defects in Epstein–Barr virus (EBV)-specific CD8⁺ T cells. Cytolysis of P815 targets by anti-CD3-mediated redirected lysis (left panel) and cytolysis of peptide-pulsed autologous LCLs (middle panel), (cytolysis from 2 HD controls and 4 patients cytotoxic T lymphocytes done in duplicate are shown, representative of 4 independent experiments). Right panel: an example of cytolysis of healthy donor (HD) and patient (PT) peptide-pulsed autologous LCLs, with titration of effector:target ratios. (C) HD EBV-specific CD8⁺ T cells cytolysis of HD or PT LCLs. Two examples are shown, which are representative of three independent experiments.