PI3Kγ is also expressed in T cells and predominantly mediates signals downstream of G protein-coupled receptors such as chemokine receptors ( 5) ( Figure 1). Indeed, LFA-1 can also activate PI3Kδ via so called outside-in signalling ( 8). PI3Kδ is activated downstream of the TCR as well by costimulatory and cytokine receptors, that stimulate the phosphorylation of tyrosines within YXXM motifs that bind to the SH2 domains of the p85 subunit ( 7) ( Figure 1). In T cells PI3Kδ is the dominant class I PI3K isoform. Class II and class III PI3Ks use PtdIns or PtdIns (4)P as a substrate and are involved in intracellular membrane trafficking, these will not be considered here. The class I PI3Ks are heterodimeric proteins consisting of a regulatory domain (class IA PI3Ks p85, class IB PI3K p101) and a catalytic domain ( 5). The class I PI3K subfamily is comprised of class IA PI3Ks (PI3Kα, PI3Kβ, and PI3Kδ) and class the IB PI3K (PI3Kγ). Proteins with PIP 3-binding properties are hence recruited to the membrane resulting in initiation of downstream signal transduction. PIP 3 is bound by a subset of pleckstrin homology (PH) and other PIP 3-binding domains. PI3K Signalling in T CellsĬlass I PI3Ks phosphorylate the D3-position of the inositol ring of PtdIns (4,5)P 2 (PIP 2) to generate PtdIns (3,4,5) P 3 (PIP 3). Of these, the expression of CCR7 and IL7Rα (CD127) are negatively controlled by PI3Kδ signalling in a FOXO1-dependent manner and will also be considered. Cytokines and chemokines are also essential for coordinating the trafficking of lymphocytes. In this article we will review how PI3K signalling regulates T cell adhesion, migration and localisation by regulating CD62L and LFA-1 affinity, as well as how this can be targeted by PI3K inhibition. CD62L binds ligands such as Gl圜AM-1 and CD34 expressed on endothelial cells and is required for efficient naïve T cell homing to LNs through high endothelial venules (HEV). Besides LFA-1, several other adhesion molecules are involved in T cell migration, including L-selectin (CD62L) found on naïve T cell subsets and on central memory T (T CM) cells. The mechanistic regulation of LFA-1 affinity has been extensively studied since its discovery in 1981 as a target for monoclonal antibodies inhibiting cytotoxic T cell-mediated killing ( 1– 3), yet many questions remain about its precise regulation and function. LFA-1 mediates T cell transendothelial migration as well as formation of a stable immunological synapse with antigen presenting cells (APC). The major integrin expressed on T cells is Leukocyte Function-associated Antigen 1 (LFA-1), which is expressed on all subsets of T cells as well as other leukocytes, including B cells and neutrophils. During the process of T cell migration, integrins are crucial mediators of adhesion and are extended to an open high-affinity conformation following stimulation of chemokine receptors and/or T cell receptor stimulation. PI3K signalling controls numerous pathways that are involved in regulating trafficking and localisation of T cells between lymphoid system and organs, and tissues through the circulatory and lymphatic systems. These findings are relevant for our understanding of how PI3Kδ inhibitors may affect T cell redistribution and function. This review will focus on the regulation of adhesion receptors by PI3Kδ and how this contributes to T cell trafficking and localisation. Therefore, PI3Kδ can control both entry and exit of T cells from lymph nodes as well as the recruitment to and retention of T cells within inflamed tissues.
PI3Kδ also suppresses the cell surface expression of CD62L and CCR7 which controls the migration of T cells across high endothelial venules in the lymph nodes and S1PR1 which controls lymph node egress. An important function of PI3Kδ is that it acts downstream of TCR stimulation to activate the major T cell integrin, LFA-1, which controls transendothelial migration of T cells as well as their interaction with antigen-presenting cells. Furthermore, characterisation of patients with Activated PI3K Delta Syndrome (APDS) and mouse models with hyperactive PI3Kδ have shed light on how increased PI3Kδ activity affects T cell functions. PI3Kδ, the dominant PI3K isoform in T cells, has been extensively characterised using PI3Kδ mutant mouse models and PI3K inhibitors. PI3K signalling is required for activation, differentiation, and trafficking of T cells. 2Laboratory of Immune System Biology, NIAID, NIH, Bethesda, MD, United States.1Department of Pathology, University of Cambridge, Cambridge, United Kingdom.
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