scholarly journals Molecular mechanism of SHP2 activation by PD-1 stimulation

2020 ◽  
Vol 6 (5) ◽  
pp. eaay4458 ◽  
Author(s):  
M. Marasco ◽  
A. Berteotti ◽  
J. Weyershaeuser ◽  
N. Thorausch ◽  
J. Sikorska ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Escape ◽  
Complex Structure ◽  
Structural Basis ◽  
Immune Receptor ◽  
Sh2 Domains ◽  
T Cell Stimulation ◽  
Programmed Death ◽  
Programmed Death 1 ◽  
Src Homology

In cancer, the programmed death-1 (PD-1) pathway suppresses T cell stimulation and mediates immune escape. Upon stimulation, PD-1 becomes phosphorylated at its immune receptor tyrosine–based inhibitory motif (ITIM) and immune receptor tyrosine–based switch motif (ITSM), which then bind the Src homology 2 (SH2) domains of SH2-containing phosphatase 2 (SHP2), initiating T cell inactivation. The SHP2–PD-1 complex structure and the exact functions of the two SH2 domains and phosphorylated motifs remain unknown. Here, we explain the structural basis and provide functional evidence for the mechanism of PD-1-mediated SHP2 activation. We demonstrate that full activation is obtained only upon phosphorylation of both ITIM and ITSM: ITSM binds C-SH2 with strong affinity, recruiting SHP2 to PD-1, while ITIM binds N-SH2, displacing it from the catalytic pocket and activating SHP2. This binding event requires the formation of a new inter-domain interface, offering opportunities for the development of novel immunotherapeutic approaches.

scholarly journals PD-L1 degradation pathway and immunotherapy for cancer

2020 ◽  
Vol 11 (11) ◽  
Author(s):  
Qian Gou ◽  
Chen Dong ◽  
Huihui Xu ◽  
Bibimaryam Khan ◽  
Jianhua Jin ◽  
...  
Keyword(s):  
T Cell ◽  
Cancer Immunotherapy ◽  
Immune Escape ◽  
Critical Role ◽  
Degradation Pathway ◽  
T Cell Proliferation ◽  
Programmed Death ◽  
Tumor Immunosuppression ◽  
Programmed Death 1 ◽  
L1 Protein

Abstract Programmed death ligand 1 (PD-L1, CD274) is an essential immune checkpoint protein that binds to programmed death 1 (PD-1) on T-lymphocytes. T cell plays a critical role in killing cancer cells while the cancer cell exhibits immune escape by the expression of PD-L1. The binding of PD-L1 to PD-1 inhibits T cell proliferation and activity, leading to tumor immunosuppression. Increasing evidence shows that PD-L1 protein undergoes degradation in proteasomes or lysosomes by multiple pathways, leading to enhanced immunotherapy for cancer. Although some specific drugs induce PD-L1 degradation and increase antitumor activity, the combination of these drugs with PD-L1/PD-1 blockade significantly enhances cancer immunotherapy. In this review, we have discussed the interaction of PD-L1 degradation with cancer immunotherapy.

scholarly journals Critically ill COVID-19 patients exhibit hyperactive cytokine responses associated with effector exhausted senescent T cells in acute infection

2021 ◽  
Author(s):  
Angélica Arcanjo ◽  
Kamila Guimarães Pinto ◽  
Jorgete Logullo ◽  
Paulo Emílio Corrêa Leite ◽  
Camilla Cristie Barreto Menezes ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Acute Infection ◽  
Severe Pneumonia ◽  
T Cell Stimulation ◽  
Programmed Death ◽  
Type 2 Cytokines ◽  
Cytokine Levels ◽  
Programmed Death 1 ◽  
Viral Relapse

Abstract COVID-19 can progress to severe pneumonia with respiratory failure and is aggravated by the deregulation of the immune system causing an excessive inflammation including the cytokine storm. We herein report that severe acutely infected patients have high levels of both type-1 and type-2 cytokines. Our results show abnormal cytokine levels upon T cell stimulation, in a non-polarized profile. Furthermore, our findings indicate that this hyperactive cytokine response is associated with a significantly increased frequency of late-differentiated T cells with particular phenotype of effector exhausted/senescent CD28 -CD57 + cells. Interestingly, we demonstrated for the first time an increased frequency of CD3 +CD4 +CD28 -CD57 + T cells with expression of programmed death 1 (PD-1), one of the hallmarks of T cell exhaustion. These findings reveal that COVID-19 is associated with acute immunodeficiency, especially within the CD4 + T cell compartment and points to possible mechanisms of loss of clonal repertoire and susceptibility to viral relapse and reinfection events.

Critical role for programmed death 1 signaling and protein kinase B in augmented regulatory T-cell induction in cord blood

2011 ◽  
Vol 128 (6) ◽  
pp. 1369-1371 ◽  
Author(s):  
Sytze de Roock ◽  
Sanne B.E.A. Hoeks ◽  
Linda Meurs ◽  
Anouk Steur ◽  
Maarten O. Hoekstra ◽  
...  
Keyword(s):  
T Cell ◽  
Protein Kinase ◽  
Cord Blood ◽  
Regulatory T Cell ◽  
Protein Kinase B ◽  
Critical Role ◽  
Programmed Death ◽  
Cell Induction ◽  
Programmed Death 1

scholarly journals Mycoplasma bovis-Induced Inhibition of Bovine Peripheral Blood Mononuclear Cell Proliferation Is Ameliorated after Blocking the Immune-Inhibitory Programmed Death 1 Receptor

2018 ◽  
Vol 86 (3) ◽  
Author(s):  
Muhammad Suleman ◽  
Farhan S. Cyprian ◽  
Steve Jimbo ◽  
Teresia Maina ◽  
Tracy Prysliak ◽  
...  
Keyword(s):  
T Cell ◽  
Peripheral Blood ◽  
Mononuclear Cells ◽  
Lung Lavage ◽  
Mycoplasma Bovis ◽  
Peripheral Blood Mononuclear ◽  
Content Type ◽  
Programmed Death ◽  
Systemic Spread ◽  
Programmed Death 1

ABSTRACTMycoplasma bovis-induced immune suppression is a major obstacle faced by the host for controlling infections.M. bovisimpairment of antigen-specific T-cell responses is achieved through inhibiting the proliferation of peripheral blood mononuclear cells (PBMCs). This impairment may contribute to the persistence ofM. bovisinfection in various sites, including lungs, and its systemic spread to various organs such as joints, with the underlying mechanisms remaining elusive. Here, we elucidated the role of the immune-inhibitory receptor programmed death 1 (PD-1) and its ligand (PD-L1) inM. bovisinfection. Flow cytometry (FCM) analyses revealed an upregulation of PD-L1 expression on tracheal and lung epithelial cell lines afterM. bovisinfection. In addition, we found increased PD-L1 expression on purified lung lavage macrophages followingM. bovisinfection by FCM and determined its localization by immunofluorescence analysis comparing infected and control lung tissue sections. Moreover,M. bovisinfection increased the expression of the PD-1 receptor on total PBMCs and in gated CD4+and CD8+T-cell subpopulations. We demonstrated thatM. bovisinfection induced a significant decrease in CD4+PD-1INTand CD8+PD-1INTsubsets with intermediate PD-1 expression, which functioned as progenitor pools giving rise to CD4+PD-1HIGHand CD8+PD-1HIGHsubsets with high PD-1 expression levels. We blocked PD-1 receptors on PBMCs using anti-PD-1 antibody at the beginning of infection, leading to a significant restoration of the proliferation of PBMCs. Taken together, our data indicate a significant involvement of the PD-1/PD-L1 inhibitory pathway duringM. bovisinfection and its associated immune exhaustion, culminating in impaired host immune responses.

scholarly journals Cytotoxic T-Lymphocyte-Associated Antigen 4 (CTLA-4)- and Programmed Death 1 (PD-1)-Mediated Regulation of Monofunctional and Dual Functional CD4+ and CD8+ T-Cell Responses in a Chronic Helminth Infection

2019 ◽  
Vol 87 (12) ◽  
Author(s):  
Anuradha Rajamanickam ◽  
Saravanan Munisankar ◽  
Chandrakumar Dolla ◽  
Thomas B. Nutman ◽  
Subash Babu
Keyword(s):  
T Cell ◽  
T Lymphocyte ◽  
Helminth Infection ◽  
Cytotoxic T Lymphocyte ◽  
T Cell Responses ◽  
Content Type ◽  
Cell Responses ◽  
Dual Functional ◽  
Programmed Death ◽  
Programmed Death 1

ABSTRACT Chronic helminth infections are known to be associated with the modulation of antigen-specific T-cell responses. Strongyloides stercoralis infection is characterized by the downmodulation of antigen-specific Th1 and Th17 responses and the upregulation of Th2 and Th9 responses. Immune homeostasis is partially maintained by negative regulators of T-cell activation, cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) and programmed death 1 (PD-1), which dampen effector responses during chronic infections. However, their roles in S. stercoralis infection are yet to be defined. Therefore, we sought to determine the role of CTLA-4 and PD-1 in regulating CD4+ and CD8+ T-cell responses and examined the frequencies of monofunctional and dual functional Th1/T cytotoxic type 1 (Tc1), Th17/Tc17, Th2/Tc2, and Th9/Tc9 cells in S. stercoralis infection in 15 infected individuals stimulated with parasite antigen following CTLA-4 or PD-1 blockade. Our data reveal that CTLA-4 or PD-1 blockade results in significantly enhanced frequencies of monofunctional and dual functional Th1/Tc1 and Th17/Tc17 cells and, in contrast, diminishes the frequencies of monofunctional and dual functional Th2/Tc2 and Th9/Tc9 cells with parasite antigen stimulation in whole-blood cultures. Thus, we demonstrate that CTLA-4 and PD-1 limit the induction of particular T-cell subsets in S. stercoralis infection, which suggests the importance of CTLA-4 and PD-1 in immune modulation in a chronic helminth infection.

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