The adaptor protein LAT serves as an integration node for signaling pathways that drive T cell activation

Abstract

T cells are essential for the adaptive immune response to pathogens. However, dysfunctional T cell activity has been implicated in numerous diseases, including the failure of organ transplants, allergic reactions, asthma, autoimmune disorders, and coronary artery disease. T cell responses to pathogens require the induction of the primary activating receptor, the T cell receptor (TCR), along with other costimulatory and adhesion receptors. Signal transduction pathways activated downstream of these receptors drive T cell responses required for the immune response and disease progression. A key question in our understanding of the mechanism of T cell activation is how signalling pathways emanating from multiple receptors integrate together to alter T cell effector functions. One integration node for intracellular signalling is the membrane-associated adaptor protein linker for the activation of T cells or LAT. Upon stimulation of the TCR and other receptors, LAT is phosphorylated at several tyrosines residues on its cytoplasmic tail. This leads to the binding of SH2-domain containing proteins and their associated molecules and the formation of large multiprotein complexes. These dynamic and highly regulated signalling complexes facilitate the production of second messengers, activate downstream pathways, induce actin cytoskeleton polymerization, and stimulate the activity of multiple transcription factors. Thus, signalling pathways from several receptors feed into LAT, which then integrates this information and selectively induces pathways critical for T cell activation and the adaptive immune response.

Functions of the FAK family kinases in T cells: beyond actin cytoskeletal rearrangement

“…Subsequently, ZAP-70 is recruited to the TCR and activated [1, 2]. ZAP-70 phosphorylates the critical adaptor proteins, LAT and SLP-76 [1, 2, 4]. Several adaptor proteins and enzymes are then recruited to LAT and SLP-76.…”

“…These pathways influence cytokine production, proliferation, and survival. Many actin cytoskeletal-associated proteins also interact with the LAT/SLP-76 complex to induce T cell spreading, adhesion, and migration [1, 2, 4]. …”

“…These events are critical to promote adaptive immune response-mediated pathogen clearance and to induce T cell memory development. Unfortunately, dysregulation of TCR, adhesion receptor, and/or costimulatory signals also induces aberrant T cell activation that contributes to asthma, allergy, transplanted organ rejection, cardiovascular disease, autoimmune disorders, and cancer progression [1, 2, 4]. …”

Human T cells in silico: Modelling their electrophysiological behaviour in health and disease

“…After antigen-specific T cell activation, a long-lasting increase in the intracellular Ca 2+ level is required to induce effector function processes like gene expression, proliferation or cytokine production. Several studies show that this Ca 2+ influx is mediated by a depletion of intracellular Ca 2+ stores and subsequent activation of Ca 2+ -release activated Ca 2+ channels (CRAC, Orai1; (Bartelt and Houtman, 2013;Feske, 2007;Feske et al, 2005)). This cation influx is counterbalanced by several potassium outward currents in order to stabilize the membrane potential and preserve the driving force.…”

Signaling at the immune synapse: vesicular trafficking takes the stage

“…7 When phosphorylated on tyrosine residues in the cytosolic tail in response to TCR engagement, LAT acts as a scaffold for the assembly of multimolecular complexes, collectively known as the LAT signalosome, which translate TCR triggering into multiple activationinduced responses, including remodeling of the T-cell cytoskeleton and fine tuning of T-cell development and function. 8 In addition to being associated with the plasma membrane in the form of pre-existing clusters, LAT molecules also form an intracellular pool which partially colocalizes with transferrin positive recycling endosomes. 6 While both pools are recruited to the IS, with a rapid mobilization of plasma membraneassociated LAT and a more delayed mobilization for vesicular LAT, it is the intracellular pool of LAT that appears to be centrally required for full LATdependent TCR signaling.…”