Regulation of CD8 T‐cell signaling, metabolism, and cytotoxic activity by extracellular lysophosphatidic acid

Abstract

SummaryLysophosphatidic acid (LPA) is an endogenous bioactive lipid that is produced extracellularly and signals to cells via cognate LPA receptors, which are G‐protein coupled receptors (GPCRs). Mature lymphocytes in mice and humans express three LPA receptors, LPA2, LPA5, and LPA6, and work from our group has determined that LPA5 signaling by T lymphocytes inhibits specific antigen‐receptor signaling pathways that ultimately impair lymphocyte activation, proliferation, and function. In this review, we discuss previous and ongoing work characterizing the ability of an LPA‐LPA5 axis to serve as a peripheral immunological tolerance mechanism that restrains adaptive immunity but is subverted during settings of chronic inflammation. Specifically, LPA‐LPA5 signaling is found to regulate effector cytotoxic CD8 T cells by (at least) two mechanisms: (i) regulating the actin‐microtubule cytoskeleton in a manner that impairs immunological synapse formation between an effector CD8 T cell and antigen‐specific target cell, thus directly impairing cytotoxic activity, and (ii) shifting T‐cell metabolism to depend on fatty‐acid oxidation for mitochondrial respiration and reducing metabolic efficiency. The in vivo outcome of LPA5 inhibitory activity impairs CD8 T‐cell killing and tumor immunity in mouse models providing impetus to consider LPA5 antagonism for the treatment of malignancies and chronic infections.

The Emerging Role of LPA as an Oncometabolite

“…In agreement with this evidence, it was recently shown that in CD8 + T-cells, LPA/LPAR5 signalling induces metabolic reprogramming and leads to T-cell exhaustion [117,118]. Furthermore, LPA disrupts the CD8 + T-cell synapse with the target cell through activation of RhoA/mDia1 signalling, which impairs inositol 1,4,5-trisphosphate receptor type 1 (IP3R1) localisation to the immune synapse [119].…”

CTLs heterogeneity and plasticity: implications for cancer immunotherapy

“…CD8+ CTLs are cytotoxic effector cells that differentiate after the initial activation of CD8+ T cells, are essential for tumor cell clearance, and play an important role in the killing of pathogens (such as viruses and bacteria) [ 8 , 9 ]. Upon exposure to antigens presented by antigen-presenting cells (APCs), antigen-specific naïve CD8+ T cells are activated and enter a process of clonal proliferation to become CD8+ CTLs with the ability to secrete inflammatory cytokines and cytotoxic molecules [ 10 , 11 ].…”

LPA-Induced Thromboxane A2-Mediated Vasoconstriction Is Limited to Poly-Unsaturated Molecular Species in Mouse Aortas

“…Lysophosphatidic acid (LPA) is a bioactive lysophospholipid mediator found in all eukaryotic tissues and most biological fluids. LPA mediates and modulates several physiological effects ranging from the development of the nervous system to regulation of the immune response and pathophysiological events like neuropathic pain and fibrosis [1][2][3][4]. LPA also controls blood vessels, including regulation of angiogenesis, vascular wall remodeling [5], and blood pressure [6].…”