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Review
. 2022 Nov;22(11):687-700.
doi: 10.1038/s41577-022-00701-8. Epub 2022 Mar 23.

The role of PI3Kγ in the immune system: new insights and translational implications

Stephen M Lanahan  1 , Matthias P Wymann  2 , Carrie L Lucas  3
Affiliations
Review

The role of PI3Kγ in the immune system: new insights and translational implications

Stephen M Lanahan et al. Nat Rev Immunol. 2022 Nov.

Abstract

Over the past two decades, new insights have positioned phosphoinositide 3-kinase-γ (PI3Kγ) as a context-dependent modulator of immunity and inflammation. Recent advances in protein structure determination and drug development have allowed for generation of highly specific PI3Kγ inhibitors, with the first now in clinical trials for several oncology indications. Recently, a monogenic immune disorder caused by PI3Kγ deficiency was discovered in humans and modelled in mice. Human inactivated PI3Kγ syndrome confirms the immunomodulatory roles of PI3Kγ and strengthens newly defined roles of this molecule in modulating inflammatory cytokine release in macrophages. Here, we review the functions of PI3Kγ in the immune system and discuss how our understanding of its potential as a therapeutic target has evolved.

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Conflict of interest statement

Competing interests

The authors declare no competing interests.

Figures

Figure 1.
Figure 1.. Context-dependent signaling of PI3Kγ complexes.
PI3Kγ is heterodimer composed of a catalytic p110γ (encoded by PIK3CG) and either a p101 (encoded by PIK3R5)or a p84 (also known as p87PIKAP; encoded by PIK3R6), adaptor subunit. When activated, PI3Kγ transfers the γ-phosphate of ATP to PtdIns(4,5)P2 (PIP2) to produce PtdIns(3,4,5)P3 (PIP3), which serves as a docking site for effector proteins with a pleckstrin homology (PH) domain, such as 3-phosphoinositide-dependent protein kinase 1 (PDPK1), protein kinase B (PKB/AKT), and Stress-Activated Protein Kinase-Interacting Protein (SIN1) associated with the mechanistic target of rapamycin (mTOR) complex 2 (TORC2),, and the TEC family kinases (TEC, BTK, ITK/EMT/TSK, BMX and TXK/RLK) which contain a PH–Tec homology domain (PHTH). AKT is activated by the concerted action of PDK1 and TORC2 which phosphorylate T308 and S473 of AKT, respectively. AKT then activates TORC1 and IκB kinase (IKK) and inhibits glycogen synthase kinase 3β (GSK3β) and nuclear translocation of forkhead box proteins O1 and O3 (FOXO 1/3), and controls numerous other targets that modulate immune responses and inflammation. The control of PI3Kγ function and activation can occur via distinct mechanisms. (1) G protein-coupled receptors (GPCR) dissociate trimeric G proteins to release the Gβγ subunit, which enhances p110γ lipid kinase activity when bound to either the p101 or p84 adaptor protein (2) When p84 is associated with p110γ, binding of GTP-loaded RAS via the p110γ RAS-binding domain (RBD) is mandatory for PI3Kγ function, while p101-p110γ complexes are resistant to RAS inactivation.,, It has been suggested that p84- and p101-p110γ complexes produce distinct functional pools of PIP3, and that p84-p110γ operate in cholesterol-rich microdomains in a strictly RAS-GTP-dependent manner,. (3) Clustering of the high affinity IgE receptor (FcεRI) triggers a protein tyrosine kinase (PTK) cascade culminating in phospholipase Cγ (PLCγ) activation, which converts PIP2 to diacylglycerol (DAG) and inositol 1,4,5-trisphosphate (IP3). The latter initiates Ca2+-release through IP3 receptors on Ca2+ stores. Depletion of Ca2+ stores then triggers the influx of extracellular Ca2+, leading to a dramatic increase of the cytosolic Ca2+ concentration and the activation of protein kinase Cβ (PKCβ). PKCβ phosphorylates p110γ on S582 in the helical domain (see Figure 2 for structural information). This renders p110γ active but eliminates p84-binding and GPCR input. (4) The engagement of Toll-like receptors (TLR4) leads to endocytosis of RAS-related protein 8 (RAB8) and lipoprotein-receptor-related protein 1 (LRP1) to endosomal compartments, where the RBD of p110γ interacts with RAB8 and p101 binds to the tail of LRP1. This complex has been claimed to modulate pro- (IL-6) and anti- (IL-10) inflammatory outputs of TORC1 signaling and IL-12 expression via regulation of GSK3β activity. (5) In cardiomyocytes and adipocytes, p110γ acts as a scaffold for protein kinase A (PKA) and phosphodiesterase 3B (PDE3B). N-terminally associated PKA inhibits p110γ by phosphorylation of T1024 in the catalytic domain of p110γ. In response to myocardial insults, the p84 adaptor subunit is believed to be replaced by p101, correlating with changes in the p110γ scaffolding function. Green arrows denote activation, blunt red arrows denote inhibition, dashed lines indicate indirect, multi-step processes, black arrows indicate a process, such as recruitment, chemical conversion or the enforcement of a process (such as endocytosis).
Figure 2:
Figure 2:. PI3Kγ complex, regulation and mutations in human patients.
The catalytic subunit of PI3Kγ, p110γ, interacts with the p101 adapter subunit (pale green, left) or alternatively with p84 (putative interaction indicated by dotted line). GTP-bound Ras (maroon, right) binds to the Ras-binding domain (RBD, light magenta) of p110γ and contributes to docking of the complex to the plasma membrane. Regulatory phosphorylation sites are depicted as enlarged red spheres located at the Cα of the respective amino acid and are labelled with tags with a red background: in the helical domain (yellow), Ser582 can be phosphorylated by PKCβ activated by FcεRI engagement, resulting in PI3Kγ activation and dissociation of p84. The phosphorylation of Thr1024 by PKA inactivates PI3Kγ. The close by loss of function mutation Arg1021Pro (labelled as yellow enlarged spheres and yellow tags) was first reported in a human patient with a PI3Kγ deficiency,,–. The Asn1085Ser mutation in the kinase domain (marine) close to the ATP-binding site and the Arg49Ser mutation (obscured, see arrow) in the adapter binding domain (ABD) were found in a biallelic patient with immunodeficiencies. The above PI3Kγ interaction model was composed from coordinates in pdb IDs 7MEZ (p101-p110γ), 1E8X (ATP-p110γ), and 1HE8 (Ras-GTP-p110γ).
Figure 3:
Figure 3:. involvement of PI3Kγ and PI3Kβ in progression of atherosclerosis.
Atherosclerosis is initiated by an excessive uptake of degenerated and oxidized LDL (LDLox) by scavenger receptors (SR/CD36) of macrophages in the intima. This, and PI3Kγ-dependent fluid-phase pinocytosis of LDL, leads to macrophage activation (PI3Kγ-mediated events are marked by circles labelled with “γ”). Activated macrophages release TNF and chemokines including monocyte chemoattractant protein1 (MCP1, also known as CCL2) . The released TNF triggers the presentation of cell adhesion molecules such as E- and P-selectin (not shown), as well as integrins (VCAM-1, ICAM-1) on endothelial cells, which promote adhesion and diapedesis of monocytes that are stimulated by binding of MCP-1 to C-C chemokine receptor type 2 (CCR2) and 5 (CCR5). In the tissue, they later differentiate to macrophages and form foam cells through saturation with LDLox. These processes result in an inflammatory environment where CCL21 and CCL19 is produced by a variety of immune cells in the intima, inducing the extravasation of CD4+ T cells into the tissue,,. Disintegration of foam cells results in fatty streaks, rendering the endothelial layer susceptible to ruptures, which are promoted by angiotensin II-dependent hypertension, and precede plaque formation., Loss of endothelial cells (represented here as a gap in the endothelium), exposure of extracellular matrix proteins (collagen, fibronectin), initiation of the blood coagulation cascade and the release of ADP from damaged cells collectively trigger platelet activation via the G protein-coupled receptors (GPCRs, such as the ADP receptor P2Y12 and the Thrombin receptor). Platelet activation and a shape change from the resting, discoid form to a spiky, spider-like cell promote the intrinsic blood coagulation pathway, thrombus formation and eventually vascular occlusion.,,– As indicated, micro-aggregation of platelets triggered by ADP requires PI3Kγ and PI3Kβ, and platelet-matrix interactions via glycoprotein VI (GPVI) and αIIb3, as well as thrombin receptor, signaling, which partially depends on PI3Kβ. Green arrows denote activation, Black arrows indicate a process, such as recruitment or translocation.
Figure 4:
Figure 4:. Shared features of immunodeficiency and immunopathology from PI3Kγ deficiency in humans and mice.
PI3Kγ deficiency results in both immunodeficiency and immunopathology. On the one hand, susceptibility to infection and poor vaccine responses are observed, which are associated with weak adaptive immune responses. Deficient T cell activation upon TCR stimulation occurs in PI3Kγ knockout mice as well as in humans with PI3Kγ deficiency, and this results in reduced proliferation and cytokine secretion by T cells, particularly in contexts of sub-optimal stimulation. T-cells are important contributors to immunocompetence and provide help for optimal B cell responses; therefore, defective effector T cell functions likely play a role in the poor humoral immunity that is observed in these patients. However, the direct effect of PI3Kγ deficiency on B cells has not yet been assessed. On the other hand, immunopathology (here defined as immune-mediated tissue damage) caused by PI3Kγ deficiency, which presents as pneumonitis and colitis in patients and has been investigated in mouse models with regards to its potential to facilitate anti-tumor immunity, appears to have a distinct mechanism which is yet to be fully deciphered. However, two contributing factors include heightened secretion of cytokines such as IL-12/IL-23 by activated myeloid cells and elevated levels of CXCL10 in the serum, resulting in excessive T cell infiltration to barrier tissues via CXCR3 receptor activation. Although both aspects of PI3Kγ-deficiency (immunodeficiency and immune-mediated tissue damage) were observed together in PI3Kγ-deficient patients, future mechanistic studies in mouse models, including those involving exposure to natural microbiota, will reveal a more holistic picture of how PI3Kγ promotes both immune competence and barrier tissue homeostasis.
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