Structural insight into T cell coinhibition by PD-1H (VISTA)

Programmed death-1 homolog (PD-1H), a CD28/B7 family molecule, coinhibits T cell activation and is an attractive immunotherapeutic target for cancer and inflammatory diseases. The molecular basis of its function, however, is unknown. Bioinformatic analyses indicated that PD-1H has a very long Ig variable region (IgV)-like domain and extraordinarily high histidine content, suggesting that unique structural features may contribute to coinhibitory mechanisms. Here we present the 1.9-Å crystal structure of the human PD-1H extracellular domain. It reveals an elongated CC′ loop and a striking concentration of histidine residues, located in the complementarity-determining region-like proximal half of the molecule. We show that surface-exposed histidine clusters are essential for robust inhibition of T cell activation. PD-1H exhibits a noncanonical IgV-like topology including an extra “H” β-strand and “clamping” disulfide, absent in known IgV-like structures, that likely restricts its orientation on the cell surface differently from other IgV-like domains. These results provide important insight into a molecular basis of T cell coinhibition by PD-1H.

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Mitochondrial Lon-induced mtDNA leakage contributes to PD-L1–mediated immunoescape via STING-IFN signaling and extracellular vesicles

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-001372 ◽

2020 ◽

Vol 8 (2) ◽

pp. e001372

Author(s):

An Ning Cheng ◽

Li-Chun Cheng ◽

Cheng-Liang Kuo ◽

Yu Kang Lo ◽

Han-Yu Chou ◽

...

Keyword(s):

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Protein Quality ◽

Innate Immune ◽

Oxygen Species ◽

Diagnostic Biomarker ◽

Cell Immunity ◽

Insight Into ◽

Anti Inflammation

BackgroundMitochondrial Lon is a chaperone and DNA-binding protein that functions in protein quality control and stress response pathways. The level of Lon regulates mitochondrial DNA (mtDNA) metabolism and the production of mitochondrial reactive oxygen species (ROS). However, there is little information in detail on how mitochondrial Lon regulates ROS-dependent cancer immunoescape through mtDNA metabolism in the tumor microenvironment (TME).MethodsWe explored the understanding of the intricate interplay between mitochondria and the innate immune response in the inflammatory TME.ResultsWe found that oxidized mtDNA is released into the cytosol when Lon is overexpressed and then it induces interferon (IFN) signaling via cGAS-STING-TBK1, which upregulates PD-L1 and IDO-1 expression to inhibit T-cell activation. Unexpectedly, upregulation of Lon also induces the secretion of extracellular vehicles (EVs), which carry mtDNA and PD-L1. Lon-induced EVs further induce the production of IFN and IL-6 from macrophages, which attenuates T-cell immunity in the TME.ConclusionsThe levels of mtDNA and PD-L1 in EVs in patients with oral cancer function as a potential diagnostic biomarker for anti-PD-L1 immunotherapy. Our studies provide an insight into the immunosuppression on mitochondrial stress and suggest a therapeutic synergy between anti-inflammation therapy and immunotherapy in cancer.

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Staphylococcal Exotoxins and Nasal Polyposis: Analysis of Systemic and Local Responses

American Journal of Rhinology ◽

10.1177/194589240501900401 ◽

2005 ◽

Vol 19 (4) ◽

pp. 327-333 ◽

Cited By ~ 52

Author(s):

Anju Tripathi ◽

Robert Kern ◽

David B. Conley ◽

Kristin Seiberling ◽

Julie C. Klemens ◽

...

Keyword(s):

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Nasal Polyposis ◽

Immunoglobulin E ◽

Inflammatory Diseases ◽

Cell Receptor ◽

Specific Ige ◽

Sinus Surgery ◽

Ige Antibodies

Background Staphylococcal exotoxins have been implicated in the pathogenesis of several chronic inflammatory diseases including atopic dermatitis (AD), asthma, and, most recently, chronic rhinosinusitis with nasal polyposis (CRS/NP). In severe AD, these toxins act both as superantigens (SAg), triggering massive T-cell activation, and as conventional allergens, triggering toxin-specific immunoglobulin E (IgE) in the serum. In CRS/NP, evidence for both processes has been reported but it is unclear whether these processes are linked. The aim of this study was to correlate SAg activity as inferred by staphylococcal-specific T-cell receptor (TCR) V-β expansion in the polyp and blood of CRS/NP patients with staphylococcal-specific anti-IgE antibodies in the serum. Methods IgE antibodies to staphylococcal exotoxin A (SEA), staphylococcal exotoxin B (SEB), and toxic shock syndrome toxin (TSST) 1 were measured in the serum of 12 individuals with CRS/NP before functional endoscopic sinus surgery. Flow cytometry was used to analyze the SEA, SEB, and TSST-1–specific TCR V-β domains on the T cells from the polyp and blood of these patients. Results Serum SEA-, SEB-, and TSST-1-specific IgE antibodies were detected in 0/12 (0%), 6/12 (50.0%), and 9/12 (75%) of CRS/NP patients, respectively. Evidence of SAg effect in the polyp lymphocytes (TCR V-β expansion in both CD4+ and CD8+ subsets) was noted in 7/12 (58.3%) patients. Five of 6 CRS/NP patients had overlapping evidence of a systemic IgE response and TCR V-β expansion, suggestive of exposure to the same exotoxin. No patients had evidence a SAg effect in blood lymphocytes. Nine of 12 subjects also had coexistent asthma. Conclusion These results provide evidence for a local SAg effect in 7/12 (58.3%) polyp patients and establish a positive correlation of V-β expansion with the presence of corresponding toxin-specific IgE in the serum.

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The RING ubiquitin E3 RNF114 interacts with A20 and modulates NF-κB activity and T-cell activation

Cell Death and Disease ◽

10.1038/cddis.2014.366 ◽

2014 ◽

Vol 5 (8) ◽

pp. e1399-e1399 ◽

Cited By ~ 27

Author(s):

M S Rodriguez ◽

I Egaña ◽

F Lopitz-Otsoa ◽

F Aillet ◽

M P Lopez-Mato ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Zinc Finger Protein ◽

Inflammatory Diseases ◽

Negative Regulator ◽

Cell Mediated Immune Response ◽

Cycle Regulation ◽

Hybrid Screening

Abstract Accurate regulation of nuclear factor-κB (NF-κB) activity is crucial to prevent a variety of disorders including immune and inflammatory diseases. Active NF-κB promotes IκBα and A20 expression, important negative regulatory molecules that control the NF-κB response. In this study, using two-hybrid screening we identify the RING-type zinc-finger protein 114 (RNF114) as an A20-interacting factor. RNF114 interacts with A20 in T cells and modulates A20 ubiquitylation. RNF114 acts as negative regulator of NF-κB-dependent transcription, not only by stabilizing the A20 protein but also IκBα. Importantly, we demonstrate that in T cells, the effect of RNF114 is linked to the modulation of T-cell activation and apoptosis but is independent of cell cycle regulation. Altogether, our data indicate that RNF114 is a new partner of A2O involved in the regulation of NF-κB activity that contributes to the control of signaling pathways modulating T cell-mediated immune response.

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Programmed death-1–induced interleukin-10 production by monocytes impairs CD4+ T cell activation during HIV infection

Nature Medicine ◽

10.1038/nm.2106 ◽

2010 ◽

Vol 16 (4) ◽

pp. 452-459 ◽

Cited By ~ 268

Author(s):

Elias A Said ◽

Franck P Dupuy ◽

Lydie Trautmann ◽

Yuwei Zhang ◽

Yu Shi ◽

...

Keyword(s):

T Cell ◽

Hiv Infection ◽

T Cell Activation ◽

Cell Activation ◽

Interleukin 10 ◽

Cd4 T Cell ◽

Programmed Death ◽

Programmed Death 1

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Differential CD147 Functional Epitopes on Distinct Leukocyte Subsets

Frontiers in Immunology ◽

10.3389/fimmu.2021.704309 ◽

2021 ◽

Vol 12 ◽

Author(s):

Supansa Pata ◽

Sirirat Surinkaew ◽

Nuchjira Takheaw ◽

Witida Laopajon ◽

Kantinan Chuensirikulchai ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Cell Function ◽

Inflammatory Diseases ◽

Cell Contact ◽

Cell Functions ◽

Tnf Α ◽

Ifn Γ

CD147, a member of the immunoglobulin (Ig) superfamily, is widely expressed in several cell types. CD147 molecules have multiple cellular functions, such as migration, adhesion, invasion, energy metabolism and T cell activation. In particular, recent studies have demonstrated the potential application of CD147 as an effective therapeutic target for cancer, as well as autoimmune and inflammatory diseases. In this study, we elucidated the functional epitopes on CD147 extracellular domains in T cell regulation using specific monoclonal antibodies (mAbs). Upon T cell activation, the anti-CD147 domain 1 mAbs M6-1E9 and M6-1D4 and the anti-CD147 domain 2 mAb MEM-M6/6 significantly reduced surface expression of CD69 and CD25 and T cell proliferation. To investigate whether functional epitopes of CD147 are differentially expressed on distinct leukocyte subsets, PBMCs, monocyte-depleted PBMCs and purified T cells were activated in the presence of anti-CD147 mAbs. The mAb M6-1E9 inhibited T cell functions via activation of CD147 on monocytes with obligatory cell-cell contact. Engagement of the CD147 epitope by the M6-1E9 mAb downregulated CD80 and CD86 expression on monocytes and IL-2, TNF-α, IFN-γ and IL-17 production in T cells. In contrast, the mAb M6-1D4 inhibited T cell function via activation of CD147 on T cells by downregulating IL-2, TNF-α and IFN-γ. Herein, we demonstrated that certain epitopes of CD147, expressed on both monocytes and T cells, are involved in the regulation of T cell activation.

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Diversification of CD1 molecules shapes lipid antigen selectivity

10.1101/2020.11.10.377556 ◽

2020 ◽

Author(s):

Nicole M. Paterson ◽

Hussein Al-Zubieri ◽

Matthew F. Barber

Keyword(s):

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Vaccine Development ◽

Structural Features ◽

Lipid Binding ◽

Primate Species ◽

Species Variation ◽

Mhc Molecules ◽

Host Pathogen

AbstractMolecular studies of host-pathogen evolution have largely focused on the consequences of variation at protein-protein interaction surfaces. The potential for other microbe-associated macromolecules to promote arms race dynamics with host factors remains unclear. The cluster of differentiation 1 (CD1) family of vertebrate cell surface receptors plays a crucial role in adaptive immunity through binding and presentation of lipid antigens to T-cells. Although CD1 proteins present a variety of endogenous and microbial lipids to various T-cell types, they are less diverse within vertebrate populations than the related major histocompatibility complex (MHC) molecules. We discovered that CD1 genes exhibit a high level of divergence between simian primate species, altering predicted lipid binding properties and T-cell receptor (TCR) interactions. These findings suggest that lipid-protein conflicts have shaped CD1 genetic variation during primate evolution. Consistent with this hypothesis, multiple primate CD1 family proteins exhibit signatures of repeated positive selection at surfaces impacting antigen presentation, binding pocket morphology, and TCR accessibility. Using a molecular modeling approach, we observe that inter-species variation as well as single mutations at rapidly-evolving sites in CD1a drastically alter predicted lipid binding and structural features of the T-cell recognition surface. We further show that alterations in both endogenous and microbial lipid binding affinities influence the ability of CD1a to undergo antigen swapping required for T-cell activation. Together these findings establish lipid-protein interactions as a critical force of host-pathogen conflict and inform potential strategies for lipid-based vaccine development.

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Cellular and molecular basis of human gamma delta T cell activation. Role of accessory molecules in alloactivation.

Journal of Clinical Investigation ◽

10.1172/jci117654 ◽

1995 ◽

Vol 95 (1) ◽

pp. 296-303 ◽

Cited By ~ 25

Author(s):

M Takamizawa ◽

F Fagnoni ◽

A Mehta-Damani ◽

A Rivas ◽

E G Engleman

Keyword(s):

T Cell ◽

T Cell Activation ◽

Molecular Basis ◽

Cell Activation ◽

Gamma Delta ◽

Accessory Molecules ◽

Gamma Delta T Cell

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Delicate Role of PD-L1/PD-1 Axis in Blood Vessel Inflammatory Diseases: Current Insight and Future Significance

International Journal of Molecular Sciences ◽

10.3390/ijms21218159 ◽

2020 ◽

Vol 21 (21) ◽

pp. 8159

Author(s):

Priya Veluswamy ◽

Max Wacker ◽

Maximilian Scherner ◽

Jens Wippermann

Keyword(s):

T Cell ◽

Blood Vessel ◽

T Cell Activation ◽

Immune Checkpoint ◽

Cell Activation ◽

Inflammatory Diseases ◽

Vascular Inflammation ◽

Experimental Models ◽

Cell Immunity

Immune checkpoint molecules are the antigen-independent generator of secondary signals that aid in maintaining the homeostasis of the immune system. The programmed death ligand-1 (PD-L1)/PD-1 axis is one among the most extensively studied immune-inhibitory checkpoint molecules, which delivers a negative signal for T cell activation by binding to the PD-1 receptor. The general attributes of PD-L1’s immune-suppressive qualities and novel mechanisms on the barrier functions of vascular endothelium to regulate blood vessel-related inflammatory diseases are concisely reviewed. Though targeting the PD-1/PD-L1 axis has received immense recognition—the Nobel Prize in clinical oncology was awarded in the year 2018 for this discovery—the use of therapeutic modulating strategies for the PD-L1/PD-1 pathway in chronic inflammatory blood vessel diseases is still limited to experimental models. However, studies using clinical specimens that support the role of PD-1 and PD-L1 in patients with underlying atherosclerosis are also detailed. Of note, delicate balances in the expression levels of PD-L1 that are needed to preserve T cell immunity and to curtail acute as well as chronic infections in underlying blood vessel diseases are discussed. A significant link exists between altered lipid and glucose metabolism in different cells and the expression of PD-1/PD-L1 molecules, and its possible implications on vascular inflammation are justified. This review summarizes the most recent insights concerning the role of the PD-L1/PD-1 axis in vascular inflammation and, in addition, provides an overview exploring the novel therapeutic approaches and challenges of manipulating these immune checkpoint proteins, PD-1 and PD-L1, for suppressing blood vessel inflammation.

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