scholarly journals Quantifying signal persistence in the T cell signaling network using an optically controllable antigen receptor

2020 ◽  
Author(s):  
Michael J Harris ◽  
Muna Fuyal ◽  
John R James
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Signaling ◽  
Antigen Receptor ◽  
T Cell Signaling ◽  
Signaling Dynamics ◽  
Efficient Detection ◽  
Infected Cells ◽  
Receptor Input ◽  
Antigen Presenting

SUMMARYT cells discriminate between healthy and infected cells with remarkable sensitivity when mounting an immune response. It has been hypothesized that this efficient detection requires combining signals from discrete antigen-presenting cell interactions into a more potent response, requiring T cells to maintain a ‘memory’ of previous encounters. To quantify the magnitude of this phenomenon, we have developed an antigen receptor that is both optically and chemically tunable, providing control over the initiation, duration, and intensity of intracellular T-cell signaling within physiological cell conjugates. We observe very limited persistence within the T cell intracellular network on disruption of receptor input, with signals dissipating entirely in ~15 minutes, and directly confirm that sustained proximal receptor signaling is required to maintain active gene transcription. Our data suggests that T cells are largely incapable of integrating discrete antigen receptor signals but instead simply accumulate the output of gene expression. By engineering optical control in a clinically relevant chimeric antigen receptor, we show that this limited signal persistence can be exploited to increase the activation of primary T cells by ~3-fold by using pulsatile stimulation. Our results are likely to apply more generally to the signaling dynamics of other cellular networks.

scholarly journals Specific Signaling Pathways Triggered by IL-2 in Human Vγ9Vδ2 T Cells: An Amalgamation of NK and αβ T Cell Signaling

2003 ◽  
Vol 171 (10) ◽  
pp. 5225-5232 ◽  
Author(s):  
Virginie Lafont ◽  
Séverine Loisel ◽  
Janny Liautard ◽  
Sherri Dudal ◽  
Magali Sablé-teychené ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Signaling ◽  
Signaling Pathways ◽  
T Cell Signaling ◽  
Vγ9vδ2 T Cells

scholarly journals Nanoconfinement of Microvilli Alters Gene Expression and Boosts T cell Activation

2021 ◽  
Author(s):  
Morteza Aramesh ◽  
Diana Stoycheva ◽  
Ioana Sandu ◽  
Stephan J. Ihle ◽  
Tamara Zund ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
T Cell ◽  
Cell Signaling ◽  
T Cell Activation ◽  
Cell Activation ◽  
Local Environment ◽  
T Cell Signaling ◽  
Sense And Respond ◽  
Altered Gene

T cells sense and respond to their local environment at the nanoscale by forming small actin-rich protrusions, called microvilli, which play critical roles in signaling and antigen recognition, particularly at the interface with the antigen presenting cells. However, the mechanisms by which microvilli contribute to cell signaling and activation is largely unknown. Here, we present a tunable engineered system that promotes microvilli formation and T cell signaling via physical stimuli. We discovered that nanoporous surfaces favored microvilli formation, and markedly altered gene expression in T cells and promoted their activation. Mechanistically, confinement of microvilli inside of nanopores leads to size-dependent sorting of membrane-anchored proteins, specifically segregating CD45 phosphatases and T cell receptors (TCR) from the tip of the protrusions when microvilli are confined in 200 nm pores, but not in 400 nm pores. Consequently, formation of TCR nanoclustered hotspots within 200 nm pores, allows sustained and augmented signaling that prompts T cell activation even in the absence of TCR agonists. The synergistic combination of mechanical and biochemical signals on porous surfaces presents a straightforward strategy to investigate the role of microvilli in T cell signaling as well as to boost T cell activation and expansion for application in the growing field of adoptive immunotherapy.

scholarly journals Fyn-Binding Protein (Fyb)/Slp-76–Associated Protein (Slap), Ena/Vasodilator-Stimulated Phosphoprotein (Vasp) Proteins and the Arp2/3 Complex Link T Cell Receptor (Tcr) Signaling to the Actin Cytoskeleton

2000 ◽  
Vol 149 (1) ◽  
pp. 181-194 ◽  
Author(s):  
Matthias Krause ◽  
Antonio S. Sechi ◽  
Marlies Konradt ◽  
David Monner ◽  
Frank B. Gertler ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Actin Cytoskeleton ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
T Cell Signaling ◽  
Tcr Signaling ◽  
Activated T Cells ◽  
Antigen Presenting ◽  
Syndrome Protein

T cell receptor (TCR)-driven activation of helper T cells induces a rapid polarization of their cytoskeleton towards bound antigen presenting cells (APCs). We have identified the Fyn- and SLP-76–associated protein Fyb/SLAP as a new ligand for Ena/ vasodilator-stimulated phosphoprotein (VASP) homology 1 (EVH1) domains. Upon TCR engagement, Fyb/SLAP localizes at the interface between T cells and anti-CD3–coated beads, where Evl, a member of the Ena/VASP family, Wiskott-Aldrich syndrome protein (WASP) and the Arp2/3 complex are also found. In addition, Fyb/SLAP is restricted to lamellipodia of spreading platelets. In activated T cells, Fyb/SLAP associates with Ena/VASP family proteins and is present within biochemical complexes containing WASP, Nck, and SLP-76. Inhibition of binding between Fyb/SLAP and Ena/VASP proteins or WASP and the Arp2/3 complex impairs TCR-dependent actin rearrangement, suggesting that these interactions play a key role in linking T cell signaling to remodeling of the actin cytoskeleton.

scholarly journals MAP4K Family Kinases and DUSP Family Phosphatases in T-Cell Signaling and Systemic Lupus Erythematosus

Cells ◽  
2019 ◽  
Vol 8 (11) ◽  
pp. 1433 ◽  
Author(s):  
Chuang ◽  
Tan
Keyword(s):  
Systemic Lupus Erythematosus ◽  
T Cells ◽  
T Cell ◽  
Cell Signaling ◽  
T Cell Activation ◽  
Lupus Erythematosus ◽  
Cell Activation ◽  
Therapeutic Targets ◽  
T Cell Signaling ◽  
Systemic Lupus

T cells play a critical role in the pathogenesis of systemic lupus erythematosus (SLE), which is a severe autoimmune disease. In the past 60 years, only one new therapeutic agent with limited efficacy has been approved for SLE treatment; therefore, the development of early diagnostic biomarkers and therapeutic targets for SLE is desirable. Mitogen-activated protein kinase kinase kinase kinases (MAP4Ks) and dual-specificity phosphatases (DUSPs) are regulators of MAP kinases. Several MAP4Ks and DUSPs are involved in T-cell signaling and autoimmune responses. HPK1 (MAP4K1), DUSP22 (JKAP), and DUSP14 are negative regulators of T-cell activation. Consistently, HPK1 and DUSP22 are downregulated in the T cells of human SLE patients. In contrast, MAP4K3 (GLK) is a positive regulator of T-cell signaling and T-cell-mediated immune responses. MAP4K3 overexpression-induced RORγt–AhR complex specifically controls interleukin 17A (IL-17A) production in T cells, leading to autoimmune responses. Consistently, MAP4K3 and the RORγt–AhR complex are overexpressed in the T cells of human SLE patients, as are DUSP4 and DUSP23. In addition, DUSPs are also involved in either human autoimmune diseases (DUSP2, DUSP7, DUSP10, and DUSP12) or T-cell activation (DUSP1, DUSP5, and DUSP14). In this review, we summarize the MAP4Ks and DUSPs that are potential biomarkers and/or therapeutic targets for SLE.

scholarly journals Leukocyte-associated immunoglobulin-like receptor 1 inhibits T-cell signaling by decreasing protein phosphorylation in the T-cell signaling pathway

2020 ◽  
Vol 295 (8) ◽  
pp. 2239-2247 ◽  
Author(s):  
Jeoung-Eun Park ◽  
David D. Brand ◽  
Edward F. Rosloniec ◽  
Ae-Kyung Yi ◽  
John M. Stuart ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tyrosine Kinase ◽  
Cell Signaling ◽  
Signaling Pathway ◽  
T Cell Receptor ◽  
Cell Receptor ◽  
T Cell Signaling ◽  
Tcr Signaling ◽  
Cell Signaling Pathway

Multiple observations implicate T-cell dysregulation as a central event in the pathogenesis of rheumatoid arthritis. Here, we investigated mechanisms for suppressing T-cell activation via the inhibitory receptor leukocyte-associated immunoglobulin-like receptor 1 (LAIR-1). To determine how LAIR-1 affects T-cell receptor (TCR) signaling, we compared 1) T cells from LAIR-1–sufficient and –deficient mice, 2) Jurkat cells expressing either LAIR-1 mutants or C-terminal Src kinase (CSK) mutants, and 3) T cells from mice that contain a CSK transgene susceptible to chemical inhibition. Our results indicated that LAIR-1 engagement by collagen or by complement C1q (C1Q, which contains a collagen-like domain) inhibits TCR signaling by decreasing the phosphorylation of key components in the canonical T-cell signaling pathway, including LCK proto-oncogene SRC family tyrosine kinase (LCK), LYN proto-oncogene SRC family tyrosine kinase (LYN), ζ chain of T-cell receptor–associated protein kinase 70 (ZAP-70), and three mitogen-activated protein kinases (extracellular signal–regulated kinase, c-Jun N-terminal kinase 1/2, and p38). The intracellular region of LAIR-1 contains two immunoreceptor tyrosine-based inhibition motifs that are both phosphorylated by LAIR-1 activation, and immunoprecipitation experiments revealed that Tyr-251 in LAIR-1 binds CSK. Using CRISPR/Cas9-mediated genome editing, we demonstrate that CSK is essential for the LAIR-1–induced inhibition of the human TCR signal transduction. T cells from mice that expressed a PP1 analog–sensitive form of CSK (CskAS) corroborated these findings, and we also found that Tyr-251 is critical for LAIR-1's inhibitory function. We propose that LAIR-1 activation may be a strategy for controlling inflammation and may offer a potential therapeutic approach for managing autoimmune diseases.

Systematically manipulating T-cell signaling dynamics via multiple model informed open-loop controller design

2012 ◽  
Author(s):  
Jeffrey P. Perley ◽  
Judith Mikolajczak ◽  
Vu C. Dinh ◽  
Marietta L. Harrison ◽  
Gregery T. Buzzard ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Signaling ◽  
Controller Design ◽  
Open Loop ◽  
Multiple Model ◽  
T Cell Signaling ◽  
Signaling Dynamics

scholarly journals BTLA and PD-1 employ distinct phosphatases to differentially repress T cell signaling

2019 ◽  
Author(s):  
Xiaozheng Xu ◽  
Amitkumar Fulzele ◽  
Yunlong Zhao ◽  
Zijun Wu ◽  
Yanyan Hu ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Signaling ◽  
Cell Activity ◽  
Immune Checkpoints ◽  
Clinical Activity ◽  
T Cell Signaling ◽  
Tcr Signaling ◽  
Durable Response ◽  
Infected Cells ◽  
Cell Death Protein

ABSTRACTT cell-mediated destruction of tumors and virus-infected cells is restricted by co-inhibitory receptors such as programmed cell death protein 1 (PD-1). Monoclonal antibodies blocking PD-1 have produced impressive clinical activity against human cancers, but durable response is limited to a minority of patients. Previous results suggest that B and T lymphocyte attenuator (BTLA), a co-inhibitory receptor structurally related to PD-1, may contribute to the resistance to PD-1 targeted therapy and co-blockade of BTLA can enhance the efficacy of anti-PD-1 immunotherapy. However, the biochemical mechanism by which BTLA represses T cell activity and to what extent the mechanism differs from that of PD-1 is unknown. Here we examine differences in the ability of BTLA and PD-1 to recruit effector molecules and regulate T cell signaling. We show that PD-1 and BTLA recruit different tyrosine phosphatases to regulate either CD28 or T cell antigen receptor (TCR)-signaling cascades. Our data reveal unexpected disparities between two structurally related immune checkpoints and two phosphatase paralogs.

scholarly journals Models of T cell antigen receptor activation: the puzzle still remained

1970 ◽  
Vol 2 (1) ◽  
pp. 62-71
Author(s):  
Sumit Deswal
Keyword(s):  
T Cells ◽  
T Cell ◽  
Intracellular Signaling ◽  
Antigen Receptor ◽  
Infectious Agent ◽  
Receptor Activation ◽  
T Cell Antigen Receptor ◽  
Cell Antigen Receptor ◽  
Cell Antigen ◽  
Antigen Presenting

T cell antigen receptor (TCR) is a protein-complex expressed on all T cells of the immune system and is responsible for the activation of T cells when infectious agent is presented by an antigen presenting cell (APC) in the form of peptides bound to the major histocompatibility complex (pMHC). Despite numerous studies it is not clear what biochemical changes upon binding of antigen ligand to the extracellular domains of TCR leads to activation of intracellular signaling (a process known as TCR triggering). This review summarizes possible biochemical mechanisms for TCR triggering and discusses their comparative limitations and advantages in explaining various experimental observations.Keywords: T cell antigen receptor; activation; modelDOI: http://dx.doi.org/10.3126/njb.v2i1.5684Nepal Journal of Biotechnology Jan.2012, Vol.2(1): 62-71

Sign in / Sign up

Export Citation Format

Share Document