A Critical Role for the Innate Immune Signaling Molecule IRAK-4 in T Cell Activation

Despite significant recent improvements in the field of immunotherapy, cancer remains a heavy burden on patients and healthcare systems. In recent years, immunotherapies have led to remarkable strides in treating certain cancers. However, despite the success of checkpoint inhibitors and the advent of cellular therapies, novel strategies need to be explored to (1) improve treatment in patients where these approaches fail and (2) make such treatments widely and financially accessible. Vaccines based on tumor antigens (Ag) have emerged as an innovative strategy with the potential to address these areas. Here, we review the fundamental aspects relevant for the development of cancer vaccines and the critical role of dendritic cells (DCs) in this process. We first offer a general overview of DC biology and routes of Ag presentation eliciting effective T cell-mediated immune responses. We then present new therapeutic avenues specifically targeting Fc gamma receptors (FcγR) as a means to deliver antigen selectively to DCs and its effects on T-cell activation. We present an overview of the mechanistic aspects of FcγR-mediated DC targeting, as well as potential tumor vaccination strategies based on preclinical and translational studies. In particular, we highlight recent developments in the field of recombinant immune complex-like large molecules and their potential for DC-mediated tumor vaccination in the clinic. These findings go beyond cancer research and may be of relevance for other disease areas that could benefit from FcγR-targeted antigen delivery, such as autoimmunity and infectious diseases.

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Abstract 13287: Dendritic Cells Play a Critical Role in the Initiation of Atherosclerosis

Circulation ◽

10.1161/circ.130.suppl_2.13287 ◽

2014 ◽

Vol 130 (suppl_2) ◽

Author(s):

Mengyao Jin ◽

Peng Liu

Keyword(s):

Cell Proliferation ◽

Dendritic Cells ◽

T Cell ◽

T Cell Activation ◽

Cell Activation ◽

Critical Role ◽

Cell Interaction ◽

Plaque Formation ◽

T Cell Proliferation ◽

Control Group

Introduction: Dendritic cells (DCs) that are known as professional antigen-presenting cells have been found to pre-locate in non-inflammatory arterial wall and increasingly accumulate during atherosclerosis progression. Previous findings suggested that residential DCs in the intima are responsible for capturing modified lipids and forming foam cells during the initiation of atherosclerosis. Hypothesis: DC accumulation and enhanced DC-T cell interaction play a critical role in the initiation of atherosclerosis. Methods: We measured plaque formation, vascular DC accumulation and antigen-specific T cell proliferation mediated by isolated aortic cells in ApoE-/- mice, as well as DTR-CD11c/ApoE-/- or DTR-CD11b/ApoE-/- mice for conditional depletion of DCs or macrophages, respectively. A brief high-fat diet for 10 days was used as a model of initial atherosclerosis. Results: In addition to increased intimal DC accumulation and plaque formation in aortic roots, 10 days of HFD induced T cell infiltration in ApoE-/- mice, compared to those without HFD as the control. Isolated aortic cells from mice with 10-day HFD showed stronger capability in inducing antigen-specific T cell proliferation, compare to the control (HFD: 3.14±0.71%; no HFD: 1.56±0.36%; p=0.022). Single diphtheria toxin (DT) injection at day 1 yielded approximately 50% decrease in intimal DC accumulation, as well as 60% attenuation in plaque formation in DTR-CD11c/ApoE-/- mice after 10-day HFD. Capability of stimulating antigen-specific T cell proliferation was also impaired in aortic cells from DC-depleted mice (DT-treated: 1.62±0.30%; PBS-treated: 3.04±0.59%; p= 0.004), along with reduction in indirect conduction of T cell activation. In contrast, no significant changes were found in plaque formation and DC accumulation in DT-injected DTR-CD11b/ApoE-/- mice after 10 days of HFD, compared to control group. Furthermore, depletion of CD11b+ macrophages in either aortas or spleens didn’t alter capability of inducing antigen-specific T cell proliferation in DT-injected mice. Conclusions: These results suggested that vascular DCs rather than macrophages play a more important role in T cell activation and initiation of atherosclerosis.

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Involvement of both major histocompatibility complex class II alpha and beta chains in CD4 function indicates a role for ordered oligomerization in T cell activation.

Journal of Experimental Medicine ◽

10.1084/jem.182.3.779 ◽

1995 ◽

Vol 182 (3) ◽

pp. 779-787 ◽

Cited By ~ 85

Author(s):

R König ◽

X Shen ◽

R N Germain

Keyword(s):

T Cell ◽

Mhc Class Ii ◽

T Cell Activation ◽

Cell Activation ◽

Critical Role ◽

Class Ii ◽

Specific Receptor ◽

Single Class ◽

Histocompatibility Complex ◽

Beta 2

CD4 is a membrane glycoprotein on T lymphocytes that binds to the same peptide:major histocompatibility complex (MHC) class II molecule recognized by the antigen-specific receptor (TCR), thereby stabilizing interactions between the TCR and peptide;MHC class II complexes and promoting the localization of the src family tyrosine kinase p56lck into the receptor complex. Previous studies identified a solvent-exposed loop on the class II beta 2 domain necessary for binding to CD4 and for eliciting CD4 coreceptor activity. Here, we demonstrate that a second surface-exposed segment of class II is also critical for CD4 function. This site is in the alpha 2 domain, positioned in single class II heterodimers in such a way that it cannot simultaneously interact with the same CD4 molecule as the beta 2 site. The ability of mutations at either site to diminish CD4 function therefore indicates that specifically organized CD4 and/or MHC class II oligomers play a critical role in coreceptor-dependent T cell activation.

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PAH- and PCB-induced Alterations of Protein Tyrosine Kinase and Cytokine Gene Transcription in Harbor Seal (Phoca Vitulina) PBMC

Clinical and Developmental Immunology ◽

10.1080/17402520500116624 ◽

2005 ◽

Vol 12 (2) ◽

pp. 91-97 ◽

Cited By ~ 15

Author(s):

Jennifer C. C. Neale ◽

Thomas P. Kenny ◽

Ronald S. Tjeerdema ◽

M. Eric Gershwin

Keyword(s):

T Cell ◽

T Cell Activation ◽

Tyrosine Kinases ◽

Cell Activation ◽

Critical Role ◽

Harbor Seal ◽

Lymphocyte Function ◽

Altered Expression ◽

Protein Tyrosine

Mechanisms underlyingin vitroimmunomodulatory effects of polycyclic aromatic hydrocarbons (PAHs) and polychlorinated biphenyls (PCBs) were investigated in harbor seal peripheral leukocytes, via real-time PCR. We examined the relative genetic expression of the protein tyrosine kinases (PTKs)FynandItk, which play a critical role in T cell activation, and IL-2, a cytokine of central importance in initiating adaptive immune responses. IL-1, the macrophage-derived pro-inflammatory cytokine of innate immunity, was also included as a measure of macrophage function. Harbor seal PBMC were exposed to the prototypic immunotoxic PAH benzo[a]pyrene (BaP), 3,3',4,4',5,5'-hexachlorobiphenyl (CB-169), a model immunotoxic PCB, or DMSO (vehicle control). Exposure of Con A-stimulated harbor seal PBMC to both BaP and CB-169 produced significantly altered expression in all four targets relative to vehicle controls. The PTKsFynandItkwere both up-regulated following exposure to BaP and CB-169. In contrast, transcripts for IL-2 and IL-1 were decreased relative to controls by both treatments. Our findings are consistent with those of previous researchers working with human and rodent systems and support a hypothesis of contaminant-altered lymphocyte function mediated (at least in part) by disruption of T cell receptor (TCR) signaling and cytokine production.

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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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The Regulation of the CNS Innate Immune Response Is Vital for the Restoration of Tissue Homeostasis (Repair) after Acute Brain Injury: A Brief Review

International Journal of Inflammation ◽

10.4061/2010/151097 ◽

2010 ◽

Vol 2010 ◽

pp. 1-18 ◽

Cited By ~ 29

Author(s):

M. R. Griffiths ◽

P. Gasque ◽

J. W. Neal

Keyword(s):

Stem Cells ◽

Immune Response ◽

T Cell ◽

Innate Immune Response ◽

T Cell Activation ◽

Cell Activation ◽

Tissue Homeostasis ◽

Innate Immune ◽

Apoptotic Cells ◽

Treg Population

Neurons and glia respond to acute injury by participating in the CNS innate immune response. This involves the recognition and clearance of “not self ” pathogens and “altered self ” apoptotic cells. Phagocytic receptors (CD14, CD36, TLR–4) clear “not self” pathogens; neurons and glia express “death signals” to initiate apoptosis in T cells.The complement opsonins C1q, C3, and iC3b facilitate the clearance of apoptotic cells by interacting with CR3 and CR4 receptors. Apoptotic cells are also cleared by the scavenger receptors CD14, Prs-R, TREM expressed by glia. Serpins also expressed by glia counter the neurotoxic effects of thrombin and other systemic proteins that gain entry to the CNS following injury. Complement pathway and T cell activation are both regulated by complement regulatory proteins expressed by glia and neurons. CD200 and CD47 are NIRegs expressed by neurons as “don't eat me” signals and they inhibit microglial activity preventing host cell attack. Neural stem cells regulate T cell activation, increase the Treg population, and suppress proinflammatory cytokine expression. Stem cells also interact with the chemoattractants C3a, C5a, SDF-1, and thrombin to promote stem cell migration into damaged tissue to support tissue homeostasis.

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Role of Ly-6 in lymphocyte activation. II. Induction of T cell activation by monoclonal anti-Ly-6 antibodies.

Journal of Experimental Medicine ◽

10.1084/jem.164.3.709 ◽

1986 ◽

Vol 164 (3) ◽

pp. 709-722 ◽

Cited By ~ 119

Author(s):

T R Malek ◽

G Ortega ◽

C Chan ◽

R A Kroczek ◽

E M Shevach

Keyword(s):

T Cells ◽

T Cell ◽

T Cell Activation ◽

Proliferative Response ◽

Cell Activation ◽

Critical Role ◽

Lymphocyte Activation ◽

Accessory Cells ◽

Peripheral T Cells ◽

Activation Cascade

The Ly-6 locus controls the expression and/or encodes for alloantigenic specificities found primarily on subpopulations of murine T and B lymphocytes. We have recently identified and characterized a new rat mAb, D7, that recognizes a nonpolymorphic Ly-6 specificity. After crosslinking by anti-Ig reagents or by Fc receptor-bearing accessory cells, mAb D7 could induce IL-2 production from T cell hybridomas, and in the presence of PMA could trigger a vigorous proliferative response in resting peripheral T cells. The addition of mAb D7 to cultures of antigen- and alloantigen-, but not mitogen-stimulated T cells resulted in a marked augmentation of the proliferative response. A number of other well-characterized mAbs to Ly-6 locus products could also stimulate a T cell proliferative response after crosslinking by anti-Ig and in the presence of PMA. These results strongly suggest that Ly-6 molecules may play a critical role in the T cell activation cascade, either as receptors for an unidentified soluble or cell-associated ligand or as transducing molecules that modulate signals initiated by antigen stimulation of the T3-Ti complex.

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DOCK8-Deficient Mice Reveal a Crucial Role for Dendritic Cell Activity in the Initiation of the Allogeneic Response to Transfused Red Blood Cells

Blood ◽

10.1182/blood.v126.23.658.658 ◽

2015 ◽

Vol 126 (23) ◽

pp. 658-658

Author(s):

Stephanie C. Eisenbarth ◽

Jeanne E. Hendrickson ◽

Samuele Calabro ◽

Antonia Gallman

Keyword(s):

T Cells ◽

Dendritic Cells ◽

T Cell ◽

Dendritic Cell ◽

T Cell Activation ◽

Cell Activation ◽

Innate Immune ◽

Allogeneic Response ◽

Deficient Mice

Abstract The generation of antibodies against transfused red blood cells (RBCs) can pose a serious health risk, especially in chronically transfused patients requiring life-long transfusion support; yet our understanding of what immune signals or cells dictate when someone will become alloimmunized is lacking. The relative role of dendritic cells, B cells and macrophages in the induction of RBC alloimmunization remain unclear. Given the now well established role of innate immune signals in regulating adaptive immunity, understanding if and how innate immunity is triggered during transfusion may allow development of therapies to prevent alloimmunization in chronically transfused subjects such as those with myelodysplasia or hemoglobinopathies. We have established a murine model system in which we can evaluate both the role of particular innate immune stimuli as well as particular cells of the immune system in regulating the allogeneic response to transfused RBCs. A particularly useful transgenic "HOD mouse" has been engineered, which encodes a triple fusion protein and provides a unique tool to directly assess both RBC-specific T and B cell responses. This RBC-specific antigen contains the model protein antigen hen egg lysozyme (HEL) fused to chicken ovalbumin (OVA) fused to the human Duffyb blood group antigen (HEL-OVA-Duffy) as an integral membrane protein under control of the beta globin promoter. Transfusion of genetically targeted mice lacking various innate immune cells or receptors allows us to screen for important immune pathways regulating the response to allogeneic RBCs. Using these models, we recently discovered that mice lacking the GEF (guanine nucleotide exchange factor) DOCK8 fail to develop alloimmunity to transfused RBCs. Dendritic cells in these knockout mice fail to migrate to T cells due to lack of coordinated actin rearrangement governed by this GEF. Both B cell and T cell activation in the spleen to the transgenic transfused RBCs is abrogated. Inclusion of OVA in the alloantigen of the HOD mice allows us to readily study naïve CD4+ T cell activation following transfusion by using the OTII T cell receptor (TCR) transgenic mice in which essentially all T cells express one antigen receptor specific for a peptide of OVA. By tracking rounds of cell division we found that adoptively transferred OTII undergo more than 5-8 rounds of division in the spleen three days following transfusion of HOD RBCs in WT recipients. In contrast, no OTII proliferation was observed in DOCK8-deficient mice following OTII adoptive transfer and HOD RBC transfusion, suggesting that T cells are failing to receive activation signals by splenic antigen presenting cells. Our preliminary data now suggest that DOCK8-deficient dendritic cells are able to process and present RBC-derived antigens, but do not migrate to T cell zones in the spleen to prime naïve RBC-specific T cells. The need for dendritic cell migration within the spleen in the induction of alloimmunity to transfused RBCs has not been addressed; these mice allow us for the first time to answer these fundamental immunologic questions during transfusion. Future work will aim to determine how dendritic cell movement within the spleen is regulated during transfusion and the specific role of splenic dendritic cell subsets in CD4+ T cell priming to allogeneic RBCs. Disclosures No relevant conflicts of interest to declare.

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Immunotherapy using activated T cells with chemotherapy for metastatic colorectal cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2017.35.4_suppl.767 ◽

2017 ◽

Vol 35 (4_suppl) ◽

pp. 767-767

Author(s):

Yoichiro Yoshida ◽

Naoya Aisu ◽

Hideki Nagano ◽

Akira Komono ◽

Daibo Kojima ◽

...

Keyword(s):

Colorectal Cancer ◽

T Cells ◽

T Cell ◽

Metastatic Colorectal Cancer ◽

T Cell Activation ◽

Adoptive Immunotherapy ◽

Cell Activation ◽

Critical Role ◽

Activated T Cells ◽

Novel Technologies

767 Background: The programmed death-1 (PD-1), an inhibitory receptor expressed on activated T cells, is demonstrated to induce an immune-mediated response and play a critical role in tumor initiation and development. T cell activation induces effective antitumor immune response in cancer patients. Adoptive immunotherapy of cancer is evolving with the development of novel technologies that generate proliferation of large number of T cells. We evaluated the safety and efficacy of the combination of adoptive immunotherapy using αβ T cells with chemotherapy for metastatic colorectal cancer (mCRC). Methods: Seventeen patients with mCRC received XELOX + bevacizumab + ex vivo expanded αβ T lymphocytes as a first-line chemoimmunotherapy. Results: Median age of the 17 patients (6 men, 11 women) was 64 years (range:38–80). The T cell number was more than 5.0×109 for each infusion. Median progression-free survival was 15.2 months. Response rate was 80% (complete response (CR) = 23.5%, partial response (PR) = 47.1%, stable disease (SD) = 29.4% and progressive disease (PD) = 0%). Most adverse events were mild to moderate in intensity and immunotherapy-associated toxicity was minimal. Conclusions: Combination of adoptive αβ T cell immunotherapy with chemotherapy for mCRC is safe and effective.

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