PI3Kδ promotes CD4⁺ T‐cell interactions with antigen‐presenting cells by increasing LFA‐1 binding to ICAM‐1

Abstract

Activation of T lymphocytes by peptide/major histocompatibility complex on antigen-presenting cells (APCs) involves dynamic contacts between the two cells, during which T cells undergo marked morphological changes. These interactions are facilitated by integrins. Activation of the T cells increases the binding of the integrin lymphocyte function-associated antigen 1 (LFA-1) expressed by T cells to intercellular adhesion molecule (ICAM)-1 and ICAM-2 expressed by APCs. The signalling pathways that control integrin affinities are incompletely defined. The phosphoinositide 3-kinases (PI3Ks) generate second-messenger signalling molecules that control cell growth, proliferation, differentiation and trafficking. Here we show that in T cells, PI3Kδ attenuates the activation of Rac1, but sustains the activation of Rap1. Consequently, PI3Kδ increases LFA-1-dependent adhesion to form stable conjugates with APCs. Increased Rap1 activity and LFA-1 adhesion were only in part mediated by the downstream kinase Akt, suggesting the involvement of additional phosphatidylinositol(3,4,5)P3-binding proteins. These results establish a link between PI3K activity, cytoskeletal changes and integrin binding and help explain the impaired T-cell-dependent immune responses in PI3Kδ-deficient mice.

Asymmetric PI3K Activity in Lymphocytes Organized by a PI3K-Mediated Polarity Pathway

“…In view of the importance of class I PI3K molecules, particularly PI3Kδ, in antigen receptor signaling ( Fruman et al, 2017 ; Garçon and Okkenhaug, 2016 ; Garçon et al, 2008 ; Lucas et al, 2016 ), we also tested the effect of idelalisib, a PI3Kδ-specific inhibitor, and pictilisib, a pan-class I PI3K inhibitor on T cell fate, nutrient utilization, and polarity. Like LY294002, the more specific inhibition resulted in defective silencing of TCF1, reduced cell surface trafficking of Glut1, diminished glucose uptake ( Figure 3D ), and defective CD3 polarity, the latter appearing more severe in interphase cells than metaphase cells ( Figure 3E ).…”

“…Spatially segregated class I PI3K activity and accompanying cytoskeletal rearrangement is an evolutionarily conserved response to guidance cues for directed migration, axon outgrowth of neurons, immunological synapsis, apico-basal polarity, and asymmetric epithelial progenitor division ( Berzat and Hall, 2010 ; Dainichi et al, 2016 ; Engelman et al, 2006 ; Garçon and Okkenhaug, 2016 ; Garçon et al, 2008 ; Le Floc’h et al, 2013 , 2015 ; Marat and Haucke, 2016 ; Nish et al, 2017a ). Following T lymphocyte activation, focal PI3K activity and actin remodeling co-localize at the immune synapse ( Garçon and Okkenhaug, 2016 ; Garçon et al, 2008 ; Le Floc’h et al, 2013 ; Singleton et al, 2009 ). Receptor-induced actin remodeling, PI3K activity, and their associated GTPases and exchange factors can act in a self-reinforcing feedback loop to create a domain of cytoskeletal-driven polarity ( Berzat and Hall, 2010 ; Le Floc’h and Huse, 2015 ).…”

β2 Integrins—Multi-Functional Leukocyte Receptors in Health and Disease

“…Kondo and co-workers delineated that Rap-1 via Mst1/Mst2 activated NDR (Nuclear Dbf2-Related Kinase) 1 kinase [142]. In APC-binding T cells, Rap-1 activation was mediated in part by PI3Kδ [143]. Binding of semaphorin 3E to its receptor plexin D1 caused inhibition of the small GTPase Rap-1 [107].…”

Phosphoinositide 3‐kinase δ is a regulatory T‐cell target in cancer immunotherapy

“…73 PI3Kd-deficient T cells also fail to down-regulate CD62L and CCR7, wellestablished markers of naive T cells important for lymphoid homing, even upon strong stimulation in vitro. 121 PI3Kd inactivation also impairs the activation of LFA-1 in CD4 + T cells, leading to defects in cell-cell interaction, which could affect the adhesive contacts necessary for tissue infiltration, or for contact-dependent suppression 122 particularly as LFA-1 is involved in CTLA-4 transendocytosis of CD80 and CD86 from antigen-presenting cells. 103 However, a comparison of tumour-infiltrating Treg cells between wild-type and PI3Kd D910A mice does not show a consistent quantitative reduction in PI3Kd-deficient mice.…”