PI3K in T Cell Adhesion and Trafficking

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.

A CRISPR screen targeting PI3K effectors identifies RASA3 as a negative regulator of LFA-1–mediated adhesion in T cells

“…The dynamic regulation of PI3K contributes to many T cell functions, as is evident from studies of immunodeficiency resulting from either inactivating mutations in humans and kinasedeficient p110 D910A mice or activating mutations in the human activated PI3K syndrome (APDS) and hyperactive p110 E1020K mice (15)(16)(17)(18). Such studies implicated PI3K in the regulation of T cell development, trafficking (19), and differentiation (18,(20)(21)(22). PI3K is also required for the antigen-dependent adhesion of T cells to ICAMs and is involved in the induction of high-affinity LFA-1 conformations downstream of TCR stimulation (23).…”

Harnessing the immune system in the treatment of cutaneous T cell lymphomas

“…Class I, the most relevant to oncology, consists of four isoforms: α, β, δ, and γ. (271) PI3K γ and PI3Kδ are expressed in hematopoietic cells, but PI3Kδ is the dominant isoform in T cells, mediating downstream signaling of the TCR, costimulatory and cytokine receptors ( 279 ). PI3Ks phosphorylate the 3-hydroxyl group of the inositol ring found in phosphatidylinositol lipid substrates ( 280 ).…”

“…However, these murine models lack an intact immune system to understand the full effects of P13K inhibition on the microenvironment. For example, PI3K signaling is important for antigen- and chemokine-dependent effector cell trafficking to peripheral sites of inflammation through regulation of leukocyte function-associated antigen-1 (LFA-1) ( 279 ). LFA-1 is needed for transendothelial egress and establishment of immunological synapse with antigen presenting cells ( 279 ).…”

“…For example, PI3K signaling is important for antigen- and chemokine-dependent effector cell trafficking to peripheral sites of inflammation through regulation of leukocyte function-associated antigen-1 (LFA-1) ( 279 ). LFA-1 is needed for transendothelial egress and establishment of immunological synapse with antigen presenting cells ( 279 ). Therefore, PI3K inhibition may limit migration of anti-tumor effector T cells to the skin and effective engagement with antigen presenting cells thereby hindering the anti-tumor response.…”

Extranodal Natural Killer/T-Cell Lymphomas: Current Approaches and Future Directions

“…The PI3K are divided into three classes (class I, II, and III) by their structure, regulation, and lipid substrates [ 75 ]. The class I kinase isoforms PI3K-δ and PI3K-γ are vital for T-cell functioning [ 76 , 77 , 78 ]. Duvelisib is an oral dual inhibitor of PI3K-δ and PI3K-γ.…”