scholarly journals The Purinergic G Protein-Coupled Receptor 6 Inhibits Effector T Cell Activation in Allergic Pulmonary Inflammation

2011 ◽  
Vol 187 (3) ◽  
pp. 1486-1495 ◽  
Author(s):  
Giorgio Giannattasio ◽  
Shin Ohta ◽  
Joshua R. Boyce ◽  
Wei Xing ◽  
Barbara Balestrieri ◽  
...  
Keyword(s):  
T Cell ◽  
G Protein ◽  
T Cell Activation ◽  
Cell Activation ◽  
Pulmonary Inflammation ◽  
G Protein Coupled Receptor ◽  
Effector T Cell ◽  
G Protein Coupled

scholarly journals A T-cell–redirecting bispecific G-protein–coupled receptor class 5 member D x CD3 antibody to treat multiple myeloma

Blood ◽  
2020 ◽  
Vol 135 (15) ◽  
pp. 1232-1243 ◽  
Author(s):  
Kodandaram Pillarisetti ◽  
Suzanne Edavettal ◽  
Mark Mendonça ◽  
Yingzhe Li ◽  
Mark Tornetta ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
T Cells ◽  
T Cell ◽  
G Protein ◽  
T Cell Activation ◽  
Cell Activation ◽  
Plasma Cells ◽  
Phase 1 ◽  
G Protein Coupled Receptor ◽  
G Protein Coupled

Abstract T-cell–mediated approaches have shown promise in myeloma treatment. However, there are currently a limited number of specific myeloma antigens that can be targeted, and multiple myeloma (MM) remains an incurable disease. G-protein–coupled receptor class 5 member D (GPRC5D) is expressed in MM and smoldering MM patient plasma cells. Here, we demonstrate that GPRC5D protein is present on the surface of MM cells and describe JNJ-64407564, a GPRC5DxCD3 bispecific antibody that recruits CD3+ T cells to GPRC5D+ MM cells and induces killing of GPRC5D+ cells. In vitro, JNJ-64407564 induced specific cytotoxicity of GPRC5D+ cells with concomitant T-cell activation and also killed plasma cells in MM patient samples ex vivo. JNJ-64407564 can recruit T cells and induce tumor regression in GPRC5D+ MM murine models, which coincide with T-cell infiltration at the tumor site. This antibody is also able to induce cytotoxicity of patient primary MM cells from bone marrow, which is the natural site of this disease. GPRC5D is a promising surface antigen for MM immunotherapy, and JNJ-64407564 is currently being evaluated in a phase 1 clinical trial in patients with relapsed or refractory MM (NCT03399799).

scholarly journals Single-Molecule, Super-Resolution, and Functional Analysis of G Protein-Coupled Receptor Behavior Within the T Cell Immunological Synapse

2021 ◽  
Vol 8 ◽  
Author(s):  
James H. Felce ◽  
Lucia Parolini ◽  
Erdinc Sezgin ◽  
Pablo F. Céspedes ◽  
Kseniya Korobchevskaya ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
G Protein ◽  
T Cell Activation ◽  
Chemokine Receptors ◽  
Cell Activation ◽  
Immunological Synapse ◽  
Super Resolution ◽  
G Protein Coupled Receptor ◽  
G Protein Coupled

A central process in immunity is the activation of T cells through interaction of T cell receptors (TCRs) with agonistic peptide-major histocompatibility complexes (pMHC) on the surface of antigen presenting cells (APCs). TCR-pMHC binding triggers the formation of an extensive contact between the two cells termed the immunological synapse, which acts as a platform for integration of multiple signals determining cellular outcomes, including those from multiple co-stimulatory/inhibitory receptors. Contributors to this include a number of chemokine receptors, notably CXC-chemokine receptor 4 (CXCR4), and other members of the G protein-coupled receptor (GPCR) family. Although best characterized as mediators of ligand-dependent chemotaxis, some chemokine receptors are also recruited to the synapse and contribute to signaling in the absence of ligation. How these and other GPCRs integrate within the dynamic structure of the synapse is unknown, as is how their normally migratory Gαi-coupled signaling is terminated upon recruitment. Here, we report the spatiotemporal organization of several GPCRs, focusing on CXCR4, and the G protein Gαi2 within the synapse of primary human CD4+ T cells on supported lipid bilayers, using standard- and super-resolution fluorescence microscopy. We find that CXCR4 undergoes orchestrated phases of reorganization, culminating in recruitment to the TCR-enriched center. This appears to be dependent on CXCR4 ubiquitination, and does not involve stable interactions with TCR microclusters, as viewed at the nanoscale. Disruption of this process by mutation impairs CXCR4 contributions to cellular activation. Gαi2 undergoes active exclusion from the synapse, partitioning from centrally-accumulated CXCR4. Using a CRISPR-Cas9 knockout screen, we identify several diverse GPCRs with contributions to T cell activation, most significantly the sphingosine-1-phosphate receptor S1PR1, and the oxysterol receptor GPR183. These, and other GPCRs, undergo organization similar to CXCR4; including initial exclusion, centripetal transport, and lack of receptor-TCR interactions. These constitute the first observations of GPCR dynamics within the synapse, and give insights into how these receptors may contribute to T cell activation. The observation of broad GPCR contributions to T cell activation also opens the possibility that modulating GPCR expression in response to cell status or environment may directly regulate responsiveness to pMHC.

scholarly journals G Protein-Coupled Receptor Kinase 2 (GRK2) Regulates T Cell Response in a Murine Model of House Dust Mite-Induced Asthma

2021 ◽  
Vol 2 ◽  
Author(s):  
Ananth K. Kammala ◽  
Canchai Yang ◽  
Reynold A. Panettieri ◽  
Rupali Das ◽  
Hariharan Subramanian
Keyword(s):  
T Cell ◽  
Mouse Model ◽  
G Protein ◽  
House Dust ◽  
House Dust Mite ◽  
T Cell Response ◽  
Receptor Kinase ◽  
G Protein Coupled Receptor ◽  
Dust Mite ◽  
G Protein Coupled

G protein-coupled receptor kinase 2 (GRK2) is an adapter protein that modulates G protein-coupled receptor (GPCR) signaling. It also regulates the functions and activity of other intracellular proteins in many cell types. Accordingly, GRK2 is thought to contribute to disease progression by a variety of mechanisms related to its multifunctional roles. Indeed, GRK2 levels are enhanced in patient samples as well as in preclinical models of several diseases. We have previously shown that GRK2 regulates mast cell functions, and thereby contributes to exacerbated inflammation during allergic reactions. In the current study, we observed that GRK2 levels are enhanced in the lungs of human asthma patients and in mice sensitized to house dust mite extract (HDME) allergen. Consistent with these findings, interleukin (IL)-4 and IL-13 levels were reduced in the lungs of GRK2+/− mice in a HMDE mouse model of asthma. Because Th2 cells are the major source of these cytokines during asthma, we determined the role of GRK2 in regulating T cell-specific responses in our HMDE mouse model. We observed a significant reduction of airway hyperresponsiveness (AHR), lung eosinophil and lymphocyte counts, serum IgE, Th2 cytokines (IL-4 and IL-13), goblet cell hyperplasia and mucus production in mice that had reduced GRK2 expression specifically in T cells. Collectively, our studies reveal an important role for GRK2 in regulating T cell response during asthma pathogenesis and further elucidation of the mechanisms through which GRK2 modulates airway inflammation will lead to the development of new therapeutic strategies for asthma.

scholarly journals T?cell homeostasis requires G?protein-coupled receptor-mediated access to trophic signals that promote growth and inhibit chemotaxis

2005 ◽  
Vol 35 (3) ◽  
pp. 786-795 ◽  
Author(s):  
Ryan?M. Cinalli ◽  
Catherine?E. Herman ◽  
Brian?O. Lew ◽  
Heather?L. Wieman ◽  
Craig?B. Thompson ◽  
...  
Keyword(s):  
T Cell ◽  
G Protein ◽  
T Cell Homeostasis ◽  
G Protein Coupled Receptor ◽  
Cell Homeostasis ◽  
G Protein Coupled

Crucial role of P2X7 receptor for effector T cell activation in experimental autoimmune uveitis

2018 ◽  
Vol 62 (3) ◽  
pp. 398-406 ◽  
Author(s):  
Atsunobu Takeda ◽  
Hisakata Yamada ◽  
Eiichi Hasegawa ◽  
Mitsuru Arima ◽  
Shoji Notomi ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Activation ◽  
Crucial Role ◽  
P2x7 Receptor ◽  
Cell Activation ◽  
Experimental Autoimmune Uveitis ◽  
Autoimmune Uveitis ◽  
Effector T Cell ◽  
Experimental Autoimmune
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