Abstract
PI3K signalling is required for activation, differentiation, and trafficking of T cells. PI3Kδ, the dominant PI3K isoform in T cells, has been extensively characterised using PI3Kδ mutant mouse models and PI3K inhibitors. 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. 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. 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. 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. This review will focus on the regulation of adhesion receptors by PI3Kδ and how this contributes to T cell trafficking and localisation. These findings are relevant for our understanding of how PI3Kδ inhibitors may affect T cell redistribution and function.
Highlights
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
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
Signalling through class I PI3K plays important roles at multiple stages of T cell development. Loss of both p110d and p110g results in near complete ablation of thymocyte b-selection, while individual loss of p110d and p110g individually only causes minor perturbations of T cell development [9,10,11]. These findings revealed an unexpected redundancy between p110d and p110g in developing T cells and was explained by cooperative signalling from the chemokine receptor CXCR4 via p110g and pre-TCR signalling via p110d, either of which is sufficient to generate PIP3 required during thymocyte b-selection [12]
Summary
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. Several groups have generated mouse models of APDS which recapitulate many of the features of the patients, including increased susceptibility to airway infections, enlarged LNs and spleen and production of autoantibodies [37,38,39,40,41] These studies shine light on the paradox that both loss-of-function and gain-of-function of PI3Kd leads to immunodeficiency, and highlight how this pathway needs to be dynamically regulated for optimal lymphocyte development and function [42, 43]. Following insideout mediated activation by chemokines, cytokines, or TCRstimulation, LFA-1 rapidly changes conformation from its low affinity closed/bent conformation to an intermediate affinity extended conformation, where the extracellular domain is partly open, but the cytosolic domain remains closed This intermediate affinity extended conformation allows for binding to ICAM-1, which can further increase affinity through outsidein signalling resulting in the high affinity open-extended conformation (Figure 2B) reviewed in [51, 55]. Multiple other integrins are expressed in subsets of T cells, including Very Late Antigen 4 (VLA-4) (a4b1) which binds VCAM-1, in this review we will focus on the roles of LFA-1
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
