Phosphoinositides regulate the TCR/CD3 complex membrane dynamics and activation

Team: Integrative analysis of T cell activation, Batiment Burg, 5th floor, 12 rue LHOMOND, Abstract T-lymphocyte activation relies on the cognate recognition by the TCR of the MHCassociated peptide ligand (pMHC) presented at the surface of an antigen-presenting cell (APC). This leads to the dynamic formation of a cognate contact between the T lymphocyte and the APC: the immune synapse (IS). Engagement of the TCR by the pMHC in the synaptic zone induces a cascade of signaling events leading to phosphorylation and dephosphorylation of proteins and lipids, which ultimately shapes the response of T lymphocytes. Although the engagement of the T-cell receptor (TCR)takes place at the plasma membrane, the TCR/CD3 complexes and the signaling molecules involved in transduction of the TCR signal are also present in intracellular membrane pools. These pools, which are both endocytic and exocytic, have tentatively been characterized by several groups including ours. We will herein summarize what is known on the intracellular pools of TCR signaling components. We will discuss their origin and the mechanisms involved in their mobility at the IS. Finally, we will propose several hypotheses concerning the functional role(s) that these intracellular pools might play in T-cell activation. We will also discuss the tools that could be used to test these hypotheses. K E Y W O R D Sendosomes, Immune synapse, Intracellular trafficking, TCR, T lymphocyte

Section: New Hypotheses About the Function Of Vesicular Pools Of Tcr mentioning

confidence: 99%

Is there a place and role for endocytic TCR signaling?

Saveanu

Zucchetti

Evnouchidou

et al. 2019

“…Reduction in PI(4,5)P2 at the cSMAC would prevent actin recruitment and thus allow proper recruitment and secretion of cytotoxic granule . Finally, ectopic expression of the PI(4,5)P2 phosphatase Inp54p at the PM reduced the inner leaflet electrostatic membrane potential and induced CD3ε dissociation as well as increased CD3ζ phosphorylation after pMHC engagement …”

Section: Modulation Of Electrostatic Interactions In Immune Receptor mentioning

confidence: 99%

Electrostatic interactions: From immune receptor assembly to signaling

Connolly

Gagnon

2019

Our ability to mount a long-lasting and protective immune response relies on a variety of immune receptors that enable the recognition of ongoing infections, which triggers the adaptation of a myriad of immune cells. The organization of several immune receptors, such as the T cells receptor and several natural killer cell receptors, utilizes different modules for ligand recognition and signaling. These receptors require specific recognition mechanisms between the different modules in order to ensure proper assembly and function. Once assembled, immune receptors must remain inactive in the absence of ligand to prevent the onset of unwanted immune response.Indeed, several mechanisms exist to prevent aberrant immune receptor signaling in the absence of ligand to avert the initiation of uncontrolled autoimmunity. However, once a ligand is recognized, immune receptors must rapidly and specifically engage kinases to initiate highly regulated signaling cascades that lead to the initiation of transcriptional programs that dictate the immune response. Over the last decade, compelling evidence have been presented which suggest that electrostatic interactions are critical for many aspects of immune receptor functions. In the work that follows, we present an overview of the literature that have provided evidence that illustrate how electrostatic interactions regulate immune receptor assembly, inactive state, triggering, and signaling.

“…Considering the PI(4,5)P2 engine model, more clear possibility is that the increase in the amount of PI(4,5)P2 at the plasma membrane by PIP5K overexpression, will likely enhance more PI(4,5)P2 inside of the T cell microclusters, which could jam the engine (signaling microcluster). In contrast, the PI(4,5)P2 deletion restricted to the Lck 1‐12 ‐localized region augmented the TCR signaling . The report speculated that it may be due to the unbinding or CD3ε cytoplasmic domain from the inner leaflet of plasma membrane .…”

Section: A Pi(45)p2‐derived “Gasoline Engine Model” For the Sustainementioning

confidence: 96%

“…And the PI(4,5)P2 dephosphorylation by the expression of Inp54p augments the constitutive and antigen‐elicited CD3 phosphorylation as well as the antigen‐stimulated early TCR signaling pathways. Further study showed that PI(4,5)P2 depletion strongly promotes the CD3ε cytoplasmic domain dissociation from the inner leaflet of plasma membrane in live cells, thus resulting in an increased CD3 availability for interacting with Lck . Considering the PI(4,5)P2 engine model, more clear possibility is that the increase in the amount of PI(4,5)P2 at the plasma membrane by PIP5K overexpression, will likely enhance more PI(4,5)P2 inside of the T cell microclusters, which could jam the engine (signaling microcluster).…”

Section: A Pi(45)p2‐derived “Gasoline Engine Model” For the Sustainementioning

confidence: 99%

A PI(4,5)P2‐derived “gasoline engine model” for the sustained B cell receptor activation

Wan

Shaheen

et al. 2019

To efficiently initiate activation responses against rare ligands in the microenvironment, lymphocytes employ sophisticated mechanisms involving signaling amplification. Recently, a signaling amplification mechanism initiated from phosphatidylinositol (PI) 4, 5‐biphosphate [PI(4,5)P2] hydrolysis and synthesis for sustained B cell activation has been reported. Antigen and B cell receptor (BCR) recognition triggered the prompt reduction of PI(4,5)P2 density within the BCR microclusters, which led to the positive feedback for the synthesis of PI(4,5)P2 outside of the BCR microclusters. At single molecule level, the diffusion of PI(4,5)P2 was slow, allowing for the maintenance of a PI(4,5)P2 density gradient between the inside and outside of the BCR microclusters and the persistent supply of PI(4,5)P2 from outside to inside of the BCR microclusters. Here, we review studies that have contributed to uncovering the molecular mechanisms of PI(4,5)P2‐derived signaling amplification model. Based on these studies, we proposed a “gasoline engine model” in which the activation of B cell signaling inside the microclusters is similar to the working principle of burning gasoline within the engine chamber of a gasoline engine. We also discuss the evidences showing the potential universality of this model and future prospects.