"Immune TOR-opathies," a Novel Disease Entity in Clinical Immunology

Abstract

Primary immunodeficiencies (PIDs) represent a group of mostly monogenic disorders caused by loss- or gain-of-function mutations in over 340 known genes that lead to abnormalities in the development and/or the function of the immune system. However, mutations in different genes can affect the same cell-signaling pathway and result in overlapping clinical phenotypes. In particular, mutations in the genes encoding for members of the phosphoinositide3-kinase (PI3K)/AKT/mTOR/S6 kinase (S6K) signaling cascade or for molecules interacting with this pathway have been associated with different PIDs that are often characterized by the coexistence of both immune deficiency and autoimmunity. The serine/threonine kinase mechanistic/mammalian target of rapamycin (mTOR), which acts downstream of PI3K and AKT, is emerging as a key regulator of immune responses. It integrates a variety of signals from the microenvironment to control cell growth, proliferation, and metabolism. mTOR plays therefore a central role in the regulation of immune cells' differentiation and functions. Here, we review the different PIDs that share an impairment of the PI3K/AKT/mTOR/S6K pathway and we propose to name them "immune TOR-opathies" by analogy with a group of neurological disorders that has been originally defined by PB Crino and that are due to aberrant mTOR signaling (1). A better understanding of the role played by this complex intracellular cascade in the pathophysiology of "immune TOR-opathies" is crucial to develop targeted therapies.

Keywords: AKT; PI3k; S6K; immune dysregulation; kinase; mTOR; primary immunodeficiency.

Figure 1

The PI3K/AKT/mTOR/S6K pathway plays a major role in the control of immune cell homeostasis. Class IA PI3Ks are heterodimeric molecules composed of a p110 catalytic subunit (p110α, p110β, or p110δ) and a p85 regulatory subunit. In immune cells, class IA PI3Ks can be activated via multiple surface tyrosine kinase-associated receptors [e.g., BCR, TCR, TLR, CD19, ICOS, PD-1, and CTLA-4] that bear YXXM motifs in their cytoplasmic domain. In the absence of ligand binding, the TSC1/TSC2 complex negatively regulates mTORC1, and therefore protein synthesis, by converting RHEB into its inactive GDP-bound state. After receptor activation, phosphorylated YXXM motifs provide binding sites for the p85 regulatory subunit that brings the p110 catalytic subunit to the membrane, where it converts PIP₂ to PIP₃. PIP₃ serves as plasma membrane docking sites for PH-domain containing proteins, such as AKT, and its upstream activator PDK1. The activity of AKT is also positively regulated by mTORC2. Once phosphorylated, AKT inhibits the TSC1/TSC2 complex, and allows the release of GTP-bound RHEB, thereby enabling mTORC1 activation. Activated mTORC1 triggers biosynthetic pathways (protein synthesis) essential for cell proliferation, survival, and metabolism through S6Ks and 4E-BP1 phosphorylation, while inhibiting ULK1, and therefore autophagy. S6K phosphorylate numerous substrate, including ribosomal protein S6, eukaryotic translation initiation factor eIF4B, and eukaryotic elongation factor 2 (eEF2) kinase. The phosphorylation of 4E-BP1 prevents its binding to the cap-binding protein eIF4E, allowing it to participate in the formation of the eIF4F complex, which is composed of the DEAD-box RNA helicase eIF4A, the cap-binding protein eIF4E, and the large “scaffold” protein eIF4G, and which is required for the initiation of cap-dependent translation. PTEN is a negative regulator of PI3K/AKT/mTOR/S6K signaling pathway that dephosphorylates PIP₃ back to PIP₂. Red circles: phosphorylation; normal arrows: activation; blunt arrows: inhibition.