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Results: 1 to 10 of 32

Publication Record


Biological Consequences of MHC-II Expression by Tumor Cells in Cancer.
Axelrod ML, Cook RS, Johnson DB, Balko JM
(2019) Clin Cancer Res 25: 2392-2402
MeSH Terms: Animals, Antigen Presentation, Antigen-Presenting Cells, Biomarkers, CD4-Positive T-Lymphocytes, Disease Management, Disease Models, Animal, Disease Susceptibility, Gene Expression, Gene Expression Regulation, Neoplastic, Histocompatibility Antigens Class I, Histocompatibility Antigens Class II, Humans, Immunotherapy, Neoplasms, Signal Transduction
Show Abstract · Added April 15, 2019
Immunotherapy has emerged as a key pillar of cancer treatment. To build upon the recent successes of immunotherapy, intense research efforts are aimed at a molecular understanding of antitumor immune responses, identification of biomarkers of immunotherapy response and resistance, and novel strategies to circumvent resistance. These studies are revealing new insight into the intricacies of tumor cell recognition by the immune system, in large part through MHCs. Although tumor cells widely express MHC-I, a subset of tumors originating from a variety of tissues also express MHC-II, an antigen-presenting complex traditionally associated with professional antigen-presenting cells. MHC-II is critical for antigen presentation to CD4 T lymphocytes, whose role in antitumor immunity is becoming increasingly appreciated. Accumulating evidence demonstrates that tumor-specific MHC-II associates with favorable outcomes in patients with cancer, including those treated with immunotherapies, and with tumor rejection in murine models. Herein, we will review current research regarding tumor-enriched MHC-II expression and regulation in a range of human tumors and murine models, and the possible therapeutic applications of tumor-specific MHC-II.
©2018 American Association for Cancer Research.
0 Communities
1 Members
0 Resources
16 MeSH Terms
Mutations in early follicular lymphoma progenitors are associated with suppressed antigen presentation.
Green MR, Kihira S, Liu CL, Nair RV, Salari R, Gentles AJ, Irish J, Stehr H, Vicente-Dueñas C, Romero-Camarero I, Sanchez-Garcia I, Plevritis SK, Arber DA, Batzoglou S, Levy R, Alizadeh AA
(2015) Proc Natl Acad Sci U S A 112: E1116-25
MeSH Terms: Antigen-Presenting Cells, CREB-Binding Protein, Chromatin, Flow Cytometry, Histocompatibility Antigens Class II, Humans, Lymphoma, Follicular, Mutation, Neoplastic Stem Cells, Polymerase Chain Reaction
Show Abstract · Added April 15, 2015
Follicular lymphoma (FL) is incurable with conventional therapies and has a clinical course typified by multiple relapses after therapy. These tumors are genetically characterized by B-cell leukemia/lymphoma 2 (BCL2) translocation and mutation of genes involved in chromatin modification. By analyzing purified tumor cells, we identified additional novel recurrently mutated genes and confirmed mutations of one or more chromatin modifier genes within 96% of FL tumors and two or more in 76% of tumors. We defined the hierarchy of somatic mutations arising during tumor evolution by analyzing the phylogenetic relationship of somatic mutations across the coding genomes of 59 sequentially acquired biopsies from 22 patients. Among all somatically mutated genes, CREBBP mutations were most significantly enriched within the earliest inferable progenitor. These mutations were associated with a signature of decreased antigen presentation characterized by reduced transcript and protein abundance of MHC class II on tumor B cells, in line with the role of CREBBP in promoting class II transactivator (CIITA)-dependent transcriptional activation of these genes. CREBBP mutant B cells stimulated less proliferation of T cells in vitro compared with wild-type B cells from the same tumor. Transcriptional signatures of tumor-infiltrating T cells were indicative of reduced proliferation, and this corresponded to decreased frequencies of tumor-infiltrating CD4 helper T cells and CD8 memory cytotoxic T cells. These observations therefore implicate CREBBP mutation as an early event in FL evolution that contributes to immune evasion via decreased antigen presentation.
1 Communities
1 Members
0 Resources
10 MeSH Terms
Role of type I interferon signaling in human metapneumovirus pathogenesis and control of viral replication.
Hastings AK, Erickson JJ, Schuster JE, Boyd KL, Tollefson SJ, Johnson M, Gilchuk P, Joyce S, Williams JV
(2015) J Virol 89: 4405-20
MeSH Terms: Analysis of Variance, Animals, Antigen-Presenting Cells, CD8-Positive T-Lymphocytes, Flow Cytometry, Gene Expression Regulation, Hepatitis A Virus Cellular Receptor 2, Humans, Interferon Type I, Metapneumovirus, Mice, Mice, Inbred C57BL, Mice, Knockout, Oximetry, Paramyxoviridae Infections, Real-Time Polymerase Chain Reaction, Receptors, Virus, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, Virus Replication
Show Abstract · Added October 2, 2015
UNLABELLED - Type I IFN signaling, which is initiated through activation of the alpha interferon receptor (IFNAR), regulates the expression of proteins that are crucial contributors to immune responses. Paramyxoviruses, including human metapneumovirus (HMPV), have evolved mechanisms to inhibit IFNAR signaling, but the specific contribution of IFNAR signaling to the control of HMPV replication, pathogenesis, and adaptive immunity is unknown. We used IFNAR-deficient (IFNAR(-/-)) mice to assess the effect of IFNAR signaling on HMPV replication and the CD8(+) T cell response. HMPV-infected IFNAR(-/-) mice had a higher peak of early viral replication but cleared the virus with kinetics similar to those of wild-type (WT) mice. However, IFNAR(-/-) mice infected with HMPV displayed less airway dysfunction and lung inflammation. CD8(+) T cells of IFNAR(-/-) mice after HMPV infection expressed levels of the inhibitory receptor programmed death 1 (PD-1) similar to those of WT mice. However, despite lower expression of inhibitory programmed death ligand 1 (PD-L1), HMPV-specific CD8(+) T cells of IFNAR(-/-) mice were more functionally impaired than those of WT mice and upregulated the inhibitory receptor Tim-3. Analysis of the antigen-presenting cell subsets in the lungs revealed that the expansion of PD-L1(low) dendritic cells (DCs), but not PD-L1(high) alveolar macrophages, was dependent on IFNAR signaling. Collectively, our results indicate a role for IFNAR signaling in the early control of HMPV replication, disease progression, and the development of an optimal adaptive immune response. Moreover, our findings suggest an IFNAR-independent mechanism of lung CD8(+) T cell impairment.
IMPORTANCE - Human metapneumovirus (HMPV) is a leading cause of acute respiratory illness. CD8(+) T cells are critical for clearing viral infection, yet recent evidence shows that HMPV and other respiratory viruses induce CD8(+) T cell impairment via PD-1-PD-L1 signaling. We sought to understand the role of type I interferon (IFN) in the innate and adaptive immune responses to HMPV by using a mouse model lacking IFN signaling. Although HMPV titers were higher in the absence of type I IFN, virus was nonetheless cleared and mice were less ill, indicating that type I IFN is not required to resolve HMPV infection but contributes to pathogenesis. Further, despite lower levels of the inhibitory ligand PD-L1 in mice lacking type I IFN, CD8(+) T cells were more impaired in these mice than in WT mice. Our data suggest that specific antigen-presenting cell subsets and the inhibitory receptor Tim-3 may contribute to CD8(+) T cell impairment.
Copyright © 2015, American Society for Microbiology. All Rights Reserved.
0 Communities
1 Members
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20 MeSH Terms
DC isoketal-modified proteins activate T cells and promote hypertension.
Kirabo A, Fontana V, de Faria AP, Loperena R, Galindo CL, Wu J, Bikineyeva AT, Dikalov S, Xiao L, Chen W, Saleh MA, Trott DW, Itani HA, Vinh A, Amarnath V, Amarnath K, Guzik TJ, Bernstein KE, Shen XZ, Shyr Y, Chen SC, Mernaugh RL, Laffer CL, Elijovich F, Davies SS, Moreno H, Madhur MS, Roberts J, Harrison DG
(2014) J Clin Invest 124: 4642-56
MeSH Terms: Aged, Aldehydes, Angiotensin II, Animals, Antigen-Presenting Cells, B7-1 Antigen, B7-2 Antigen, Cell Proliferation, Cohort Studies, Dendritic Cells, Female, Gene Expression Regulation, Humans, Hypertension, Inflammation, Interleukin-17, Interleukin-1beta, Interleukin-23, Interleukin-6, Kidney, Lymphocyte Activation, Male, Mice, Mice, Transgenic, Middle Aged, Oxidative Stress, Oxygen, Superoxides, T-Lymphocytes
Show Abstract · Added September 26, 2014
Oxidative damage and inflammation are both implicated in the genesis of hypertension; however, the mechanisms by which these stimuli promote hypertension are not fully understood. Here, we have described a pathway in which hypertensive stimuli promote dendritic cell (DC) activation of T cells, ultimately leading to hypertension. Using multiple murine models of hypertension, we determined that proteins oxidatively modified by highly reactive γ-ketoaldehydes (isoketals) are formed in hypertension and accumulate in DCs. Isoketal accumulation was associated with DC production of IL-6, IL-1β, and IL-23 and an increase in costimulatory proteins CD80 and CD86. These activated DCs promoted T cell, particularly CD8+ T cell, proliferation; production of IFN-γ and IL-17A; and hypertension. Moreover, isoketal scavengers prevented these hypertension-associated events. Plasma F2-isoprostanes, which are formed in concert with isoketals, were found to be elevated in humans with treated hypertension and were markedly elevated in patients with resistant hypertension. Isoketal-modified proteins were also markedly elevated in circulating monocytes and DCs from humans with hypertension. Our data reveal that hypertension activates DCs, in large part by promoting the formation of isoketals, and suggest that reducing isoketals has potential as a treatment strategy for this disease.
3 Communities
6 Members
0 Resources
29 MeSH Terms
Antibody-functionalized peptidic membranes for neutralization of allogeneic skin antigen-presenting cells.
Wen Y, Liu W, Bagia C, Zhang S, Bai M, Janjic JM, Giannoukakis N, Gawalt ES, Meng WS
(2014) Acta Biomater 10: 4759-4767
MeSH Terms: Amino Acid Sequence, Animals, Antibodies, Antigen-Presenting Cells, Cell Membrane, Computer Systems, Emulsions, Female, Graft Rejection, Immobilized Proteins, Immunoglobulin G, Interferon-gamma, Lymph Nodes, Mice, Inbred BALB C, Mice, Inbred C57BL, Molecular Sequence Data, Nanoparticles, Neutralization Tests, Peptides, Skin, Skin Transplantation, Spectroscopy, Near-Infrared, T-Lymphocytes, Transplantation, Homologous
Show Abstract · Added April 2, 2019
We report herein application of an in situ material strategy to attenuate allograft T cell responses in a skin transplant mouse model. Functionalized peptidic membranes were used to impede trafficking of donor antigen-presenting cells (dAPCs) from skin allografts in recipient mice. Membranes formed by self-assembling peptides (SAPs) presenting antibodies were found to remain underneath grafted skins for up to 6 days. At the host-graft interface, dAPCs were targeted by using a monoclonal antibody that binds to a class II major histocompatibility complex (MHC) molecule (I-A(d)) expressed exclusively by donor cells. Using a novel cell labeling near-infrared nanoemulsion, we found more dAPCs remained in allografts treated with membranes loaded with anti-I-A(d) antibodies than without. In vitro, dAPCs released from skin explants were found adsorbed preferentially on anti-I-A(d) antibody-loaded membranes. Recipient T cells from these mice produced lower concentrations of interferon-gamma cultured ex vivo with donor cells. Taken together, the data indicate that the strategy has the potential to alter the natural course of rejection immune mechanisms in allogeneic transplant models.
Copyright © 2014 Acta Materialia Inc. Published by Elsevier Ltd. All rights reserved.
0 Communities
1 Members
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MeSH Terms
Detection of rare antigen-presenting cells through T cell-intrinsic meandering motility, mediated by Myo1g.
Gérard A, Patino-Lopez G, Beemiller P, Nambiar R, Ben-Aissa K, Liu Y, Totah FJ, Tyska MJ, Shaw S, Krummel MF
(2014) Cell 158: 492-505
MeSH Terms: Animals, Antigen-Presenting Cells, Cell Membrane, Cell Movement, Immunologic Surveillance, Lymph Nodes, Mice, Minor Histocompatibility Antigens, Myosins, Receptors, Antigen, T-Cell, T-Lymphocytes
Show Abstract · Added January 21, 2015
To mount an immune response, T lymphocytes must successfully search for foreign material bound to the surface of antigen-presenting cells. How T cells optimize their chances of encountering and responding to these antigens is unknown. T cell motility in tissues resembles a random or Levy walk and is regulated in part by external factors including chemokines and lymph-node topology, but motility parameters such as speed and propensity to turn may also be cell intrinsic. Here we found that the unconventional myosin 1g (Myo1g) motor generates membrane tension, enforces cell-intrinsic meandering search, and enhances T-DC interactions during lymph-node surveillance. Increased turning and meandering motility, as opposed to ballistic motility, is enhanced by Myo1g. Myo1g acts as a "turning motor" and generates a form of cellular "flânerie." Modeling and antigen challenges show that these intrinsically programmed elements of motility search are critical for the detection of rare cognate antigen-presenting cells.
Copyright © 2014 Elsevier Inc. All rights reserved.
1 Communities
1 Members
0 Resources
11 MeSH Terms
Tolerant anti-insulin B cells are effective APCs.
Kendall PL, Case JB, Sullivan AM, Holderness JS, Wells KS, Liu E, Thomas JW
(2013) J Immunol 190: 2519-26
MeSH Terms: Animals, Antigen-Presenting Cells, B-Lymphocyte Subsets, Cells, Cultured, Clonal Anergy, Coculture Techniques, Diabetes Mellitus, Type 1, Immune Tolerance, Insulin Antibodies, Lymphocyte Activation, Mice, Mice, Inbred C57BL, Mice, Inbred NOD, Mice, Transgenic, Receptors, Antigen, B-Cell, T-Lymphocyte Subsets
Show Abstract · Added December 10, 2013
Autoreactive B lymphocytes that are not culled by central tolerance in the bone marrow frequently enter the peripheral repertoire in a state of functional impairment, termed anergy. These cells are recognized as a liability for autoimmunity, but their contribution to disease is not well understood. Insulin-specific 125Tg B cells support T cell-mediated type 1 diabetes in NOD mice, despite being anergic to B cell mitogens and T cell-dependent immunization. Using this model, the potential of anergic, autoreactive B cells to present Ag and activate T cells was investigated. The data show that 1) insulin is captured and rapidly internalized by 125Tg BCRs, 2) these Ag-exposed B cells are competent to activate both experienced and naive CD4(+) T cells, 3) anergic 125Tg B cells are more efficient than naive B cells at activating T cells when Ag is limiting, and 4) 125Tg B cells are competent to generate low-affinity insulin B chain epitopes necessary for activation of diabetogenic anti-insulin BDC12-4.1 T cells, indicating the pathological relevance of anergic B cells in type 1 diabetes. Thus, phenotypically tolerant B cells that are retained in the repertoire may promote autoimmunity by driving activation and expansion of autoaggressive T cells via Ag presentation.
2 Communities
3 Members
0 Resources
16 MeSH Terms
Sculpting MHC class II-restricted self and non-self peptidome by the class I Ag-processing machinery and its impact on Th-cell responses.
Spencer CT, Dragovic SM, Conant SB, Gray JJ, Zheng M, Samir P, Niu X, Moutaftsi M, Van Kaer L, Sette A, Link AJ, Joyce S
(2013) Eur J Immunol 43: 1162-72
MeSH Terms: Amino Acid Sequence, Animals, Antigen Presentation, Antigen-Presenting Cells, Antigens, Ly, Epitopes, Histocompatibility Antigens Class I, Histocompatibility Antigens Class II, Leucyl Aminopeptidase, Membrane Proteins, Mice, Mice, Knockout, Molecular Sequence Data, Peptide Fragments, Proteomics, Sequence Analysis, Protein, T-Lymphocytes, Helper-Inducer, Tandem Mass Spectrometry
Show Abstract · Added April 18, 2013
It is generally assumed that the MHC class I antigen (Ag)-processing (CAP) machinery - which supplies peptides for presentation by class I molecules - plays no role in class II-restricted presentation of cytoplasmic Ags. In striking contrast to this assumption, we previously reported that proteasome inhibition, TAP deficiency or ERAAP deficiency led to dramatically altered T helper (Th)-cell responses to allograft (HY) and microbial (Listeria monocytogenes) Ags. Herein, we tested whether altered Ag processing and presentation, altered CD4(+) T-cell repertoire, or both underlay the above finding. We found that TAP deficiency and ERAAP deficiency dramatically altered the quality of class II-associated self peptides suggesting that the CAP machinery impacts class II-restricted Ag processing and presentation. Consistent with altered self peptidomes, the CD4(+) T-cell receptor repertoire of mice deficient in the CAP machinery substantially differed from that of WT animals resulting in altered CD4(+) T-cell Ag recognition patterns. These data suggest that TAP and ERAAP sculpt the class II-restricted peptidome, impacting the CD4(+) T-cell repertoire, and ultimately altering Th-cell responses. Together with our previous findings, these data suggest multiple CAP machinery components sequester or degrade MHC class II-restricted epitopes that would otherwise be capable of eliciting functional Th-cell responses.
© 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
0 Communities
3 Members
0 Resources
18 MeSH Terms
The structural basis of HLA-associated drug hypersensitivity syndromes.
Pompeu YA, Stewart JD, Mallal S, Phillips E, Peters B, Ostrov DA
(2012) Immunol Rev 250: 158-66
MeSH Terms: Antigen-Presenting Cells, Autoantigens, Binding Sites, Drug Hypersensitivity, HLA Antigens, Humans, Ligands, Models, Molecular, Peptides, Protein Binding, Protein Conformation, Receptors, Antigen, T-Cell, Syndrome, T-Lymphocytes, Xenobiotics
Show Abstract · Added March 30, 2020
Recent data suggest alternative mechanisms that promote human leukocyte antigen (HLA)-associated drug syndromes. Hypersensitive responses have been attributed to drug interactions with HLA molecules, peptides presented by HLA molecules and T-cell antigen receptors. Definition of an increasing number of HLA-associated drug syndromes suggests that polymorphism in the antigen-binding cleft residues influence recognition of specific drugs. Recent data demonstrate that small molecule drugs bind within the antigen-binding cleft of HLA in a manner that alters the repertoire of HLA-bound peptide ligands. This drug recognition mechanism permits presentation of self-peptides to which the host has not been tolerized. This altered repertoire mechanism is analogous to massive polyclonal T-cell responses occurring in mismatched HLA organ transplantation in which the drug in effect creates a novel HLA allele. Alteration of the self-peptide repertoire by HLA-binding small molecules may be the mechanistic basis for a diverse set of deleterious T-cell responses since the antigen-binding cleft has structural features that are compatible with binding drug-like small molecules. Small molecule drugs that bind elements of the trimolecular complex (T-cell receptor, peptide, and HLA) may cause short- and long-term adverse effects by a diverse set of mechanisms.
© 2012 John Wiley & Sons A/S.
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MeSH Terms
The inhibitory FcγRIIb modulates the inflammatory response and influences atherosclerosis in male apoE(-/-) mice.
Mendez-Fernandez YV, Stevenson BG, Diehl CJ, Braun NA, Wade NS, Covarrubias R, van Leuven S, Witztum JL, Major AS
(2011) Atherosclerosis 214: 73-80
MeSH Terms: Animals, Antigen-Presenting Cells, Antigens, Aorta, Apolipoproteins E, Atherosclerosis, B-Lymphocytes, Cytokines, Enzyme-Linked Immunosorbent Assay, Inflammation, Lipoproteins, LDL, Male, Mice, Mice, Transgenic, Receptors, IgG
Show Abstract · Added February 11, 2014
BACKGROUND - Atherosclerosis is widely accepted as an inflammatory disease involving both innate and adaptive immunity. B cells and/or antibodies have previously been shown to play a protective role against atherosclerosis. Aside from their ability to bind to antigens, antibodies can influence inflammatory responses by interacting with various Fcγ receptors on the surface of antigen presenting cells. Although studies in mice have determined that stimulatory Fcγ receptors contribute to atherosclerosis, the role of the inhibitory Fcγ receptor IIb (FcγRIIb) has only recently been investigated.
METHODS AND RESULTS - To determine the importance of FcγRIIb in modulating the adaptive immune response to hyperlipidemia, we generated FcγRIIb-deficient mice on the apoE-deficient background (apoE/FcγRIIb(-/-)). We report that male apoE/FcγRIIb(-/-) mice develop exacerbated atherosclerosis that is independent of lipid levels, and is characterized by increased antibody titers to modified LDL and pro-inflammatory cytokines in the aorta.
CONCLUSIONS - These findings suggest that antibodies against atherosclerosis-associated antigens partially protect against atherosclerosis in male apoE(-/-) mice by conveying inhibitory signals through the FcγRIIb that downregulate pro-inflammatory signaling via other immune receptors. These data are the first to describe a significant in vivo effect for FcγRIIb in modulating the cytokine response in the aorta in male apoE(-/-) mice.
Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.
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15 MeSH Terms