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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
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16 MeSH Terms
Shared peptide binding of HLA Class I and II alleles associate with cutaneous nevirapine hypersensitivity and identify novel risk alleles.
Pavlos R, McKinnon EJ, Ostrov DA, Peters B, Buus S, Koelle D, Chopra A, Schutte R, Rive C, Redwood A, Restrepo S, Bracey A, Kaever T, Myers P, Speers E, Malaker SA, Shabanowitz J, Jing Y, Gaudieri S, Hunt DF, Carrington M, Haas DW, Mallal S, Phillips EJ
(2017) Sci Rep 7: 8653
MeSH Terms: Alleles, Anti-HIV Agents, Case-Control Studies, Disease Susceptibility, Drug Hypersensitivity, Histocompatibility Antigens Class I, Histocompatibility Antigens Class II, Humans, Nevirapine, Odds Ratio, Peptides, Protein Binding, Risk Assessment, T-Lymphocytes
Show Abstract · Added March 30, 2020
Genes of the human leukocyte antigen (HLA) system encode cell-surface proteins involved in regulation of immune responses, and the way drugs interact with the HLA peptide binding groove is important in the immunopathogenesis of T-cell mediated drug hypersensitivity syndromes. Nevirapine (NVP), is an HIV-1 antiretroviral with treatment-limiting hypersensitivity reactions (HSRs) associated with multiple class I and II HLA alleles. Here we utilize a novel analytical approach to explore these multi-allelic associations by systematically examining HLA molecules for similarities in peptide binding specificities and binding pocket structure. We demonstrate that primary predisposition to cutaneous NVP HSR, seen across ancestral groups, can be attributed to a cluster of HLA-C alleles sharing a common binding groove F pocket with HLA-C*04:01. An independent association with a group of class II alleles which share the HLA-DRB1-P4 pocket is also observed. In contrast, NVP HSR protection is afforded by a cluster of HLA-B alleles defined by a characteristic peptide binding groove B pocket. The results suggest drug-specific interactions within the antigen binding cleft can be shared across HLA molecules with similar binding pockets. We thereby provide an explanation for multiple HLA associations with cutaneous NVP HSR and advance insight into its pathogenic mechanisms.
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MeSH Terms
Phenome-wide scanning identifies multiple diseases and disease severity phenotypes associated with HLA variants.
Karnes JH, Bastarache L, Shaffer CM, Gaudieri S, Xu Y, Glazer AM, Mosley JD, Zhao S, Raychaudhuri S, Mallal S, Ye Z, Mayer JG, Brilliant MH, Hebbring SJ, Roden DM, Phillips EJ, Denny JC
(2017) Sci Transl Med 9:
MeSH Terms: Alleles, Diabetes Mellitus, Type 1, Genetic Predisposition to Disease, Genome-Wide Association Study, HLA-DQ beta-Chains, Histocompatibility Antigens Class II, Humans, Polymorphism, Single Nucleotide
Show Abstract · Added March 14, 2018
Although many phenotypes have been associated with variants in human leukocyte antigen (HLA) genes, the full phenotypic impact of HLA variants across all diseases is unknown. We imputed HLA genomic variation from two populations of 28,839 and 8431 European ancestry individuals and tested association of HLA variation with 1368 phenotypes. A total of 104 four-digit and 92 two-digit HLA allele phenotype associations were significant in both discovery and replication cohorts, the strongest being and type 1 diabetes. Four previously unidentified associations were identified across the spectrum of disease with two- and four-digit HLA alleles and 10 with nonsynonymous variants. Some conditions associated with multiple HLA variants and stronger associations with more severe disease manifestations were identified. A comprehensive, publicly available catalog of clinical phenotypes associated with HLA variation is provided. Examining HLA variant disease associations in this large data set allows comprehensive definition of disease associations to drive further mechanistic insights.
Copyright © 2017, American Association for the Advancement of Science.
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3 Members
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8 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
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10 MeSH Terms
Identification of myeloid cell subsets in murine lungs using flow cytometry.
Zaynagetdinov R, Sherrill TP, Kendall PL, Segal BH, Weller KP, Tighe RM, Blackwell TS
(2013) Am J Respir Cell Mol Biol 49: 180-9
MeSH Terms: Animals, Bone Density Conservation Agents, Clodronic Acid, Dendritic Cells, Flow Cytometry, Histocompatibility Antigens Class II, Lung, Macrophage Activation, Macrophages, Alveolar, Mice, Mice, Transgenic, Monocytes
Show Abstract · Added November 14, 2013
Although the antibody-based recognition of cell-surface markers has been widely used for the identification of immune cells, overlap in the expression of markers by different cell types and the inconsistent use of antibody panels have resulted in a lack of clearly defined signatures for myeloid cell subsets. We developed a 10-fluorochrome flow cytometry panel for the identification and quantitation of myeloid cells in the lungs, including pulmonary monocytes, myeloid dendritic cells, alveolar and interstitial macrophages, and neutrophils. After the initial sorting of viable CD45(+) leukocytes, we detected three leukocyte subpopulations based on CD68 expression: CD68(-), CD68(low), and CD68(hi). Further characterization of the CD68(hi) population revealed CD45(+)/CD68(hi)/F4/80(+)/CD11b(-)/CD11c(+)/Gr1(-) alveolar macrophages and CD45(+)/CD68(hi)/F4/80(-)/CD11c(+)/Gr1(-)/CD103(+)/major histocompatibility complex (MHC) class II(hi) dendritic cells. The CD68(low) population contained primarily CD45(+)/CD68(low)/F4/80(+)/CD11b(+)/CD11c(+)/Gr1(-)/CD14(low) interstitial macrophages and CD45(+)/CD68(low)/F4/80(+)/CD11b(+)/CD11c(-)/Gr1(low)/CD14(hi) monocytes, whereas the CD68(-) population contained neutrophils (CD45(+)/CD68(-)/F4/80(-)/CD11b(+)/Gr1(hi)). The validity of cellular signatures was confirmed by a morphological analysis of FACS-sorted cells, functional studies, and the depletion of specific macrophage subpopulations using liposomal clodronate. We believe our approach provides an accurate and reproducible method for the isolation, quantification, and characterization of myeloid cell subsets in the lungs, which may be useful for studying the roles of myeloid cells during various pathological processes.
2 Communities
3 Members
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12 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.
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3 Members
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18 MeSH Terms
A mouse model of clonal CD8+ T lymphocyte-mediated alopecia areata progressing to alopecia universalis.
Alli R, Nguyen P, Boyd K, Sundberg JP, Geiger TL
(2012) J Immunol 188: 477-86
MeSH Terms: Alopecia Areata, Animals, CD8-Positive T-Lymphocytes, Hair Follicle, Histocompatibility Antigens Class I, Histocompatibility Antigens Class II, Humans, Interleukin-10, Interleukin-17, Interleukin-4, Lymphocyte Activation, Mice, Mice, Knockout, Rats, Receptors, Antigen, T-Cell, alpha-beta
Show Abstract · Added March 20, 2014
Alopecia areata is among the most prevalent autoimmune diseases, yet compared with other autoimmune conditions, it is not well studied. This in part results from limitations in the C3H/HeJ mouse and DEBR rat model systems most commonly used to study the disease, which display a low frequency and late onset. We describe a novel high-incidence model for spontaneous alopecia areata. The 1MOG244 T cell expresses dual TCRA chains, one of which, when combined with the single TCRB present, promotes the development of CD8(+) T cells with specificity for hair follicles. Retroviral transgenic mice expressing this TCR develop spontaneous alopecia areata at nearly 100% incidence. Disease initially follows a reticular pattern, with regionally cyclic episodes of hair loss and regrowth, and ultimately progresses to alopecia universalis. Alopecia development is associated with CD8(+) T cell activation, migration into the intrafollicular region, and hair follicle destruction. The disease may be adoptively transferred with T lymphocytes and is class I and not class II MHC-dependent. Pathologic T cells primarily express IFNG and IL-17 early in disease, with dramatic increases in cytokine production and recruitment of IL-4 and IL-10 production with disease progression. Inhibition of individual cytokines did not significantly alter disease incidence, potentially indicating redundancy in cytokine responses. These results therefore characterize a new high-incidence model for alopecia areata in C57BL/6J mice, the first to our knowledge to apply a monoclonal TCR, and indicate that class I MHC-restricted CD8(+) T lymphocytes can independently mediate the pathologic response.
1 Communities
1 Members
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15 MeSH Terms
Proteasomes, TAP, and endoplasmic reticulum-associated aminopeptidase associated with antigen processing control CD4+ Th cell responses by regulating indirect presentation of MHC class II-restricted cytoplasmic antigens.
Dragovic SM, Hill T, Christianson GJ, Kim S, Elliott T, Scott D, Roopenian DC, Van Kaer L, Joyce S
(2011) J Immunol 186: 6683-92
MeSH Terms: ATP-Binding Cassette Transporters, Aminopeptidases, Antigen Presentation, Antigens, Bacterial, Cytoplasm, Endoplasmic Reticulum, Histocompatibility Antigens Class II, Listeria monocytogenes, Proteasome Endopeptidase Complex, T-Lymphocytes, Helper-Inducer, Transplantation, Homologous
Show Abstract · Added March 20, 2014
Cytoplasmic Ags derived from viruses, cytosolic bacteria, tumors, and allografts are presented to T cells by MHC class I or class II molecules. In the case of class II-restricted Ags, professional APCs acquire them during uptake of dead class II-negative cells and present them via a process called indirect presentation. It is generally assumed that the cytosolic Ag-processing machinery, which supplies peptides for presentation by class I molecules, plays very little role in indirect presentation of class II-restricted cytoplasmic Ags. Remarkably, upon testing this assumption, we found that proteasomes, TAP, and endoplasmic reticulum-associated aminopeptidase associated with Ag processing, but not tapasin, partially destroyed or removed cytoplasmic class II-restricted Ags, such that their inhibition or deficiency led to dramatically increased Th cell responses to allograft (HY) and microbial (Listeria monocytogenes) Ags, both of which are indirectly presented. This effect was neither due to enhanced endoplasmic reticulum-associated degradation nor competition for Ag between class I and class II molecules. From these findings, a novel model emerged in which the cytosolic Ag-processing machinery regulates the quantity of cytoplasmic peptides available for presentation by class II molecules and, hence, modulates Th cell responses.
0 Communities
2 Members
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11 MeSH Terms
Apoptotic cells selectively suppress the Th1 cytokine interferon gamma in stimulated human peripheral blood mononuclear cells and shift the Th1/Th2 balance towards Th2.
Girkontaite I, Urbonaviciute V, Maseda D, Neubert K, Herrmann M, Voll RE
(2007) Autoimmunity 40: 327-30
MeSH Terms: Apoptosis, Autocrine Communication, Cells, Cultured, Cytokines, Histocompatibility Antigens Class II, Humans, Inflammation Mediators, Interferon-gamma, Lymphocyte Activation, Paracrine Communication, Phagocytes, Phagocytosis, Th1 Cells, Th2 Cells
Show Abstract · Added September 17, 2013
Apoptotic cells are readily recognized and engulfed by phagocytes and usually do not induce inflammation or tissue damage. Furthermore, they can actively suppress a pro-inflammatory response in phagocytes: In the presence of apoptotic cells, activated monocytes/macrophages produce more of the anti-inflammatory and immunoregulatory cytokines IL-10 and TGF-beta, but less of the pro-inflammatory cytokines TNFalpha, IL-1beta and IL-12. This immunoregulatory effect is most likely mediated by several receptors on monocytes/macrophages including the thrombospondin receptor (CD36). In addition to the modulation of cytokine secretion, apoptotic cell material inhibited the expression of MHC class II molecules on the surface of monocytes/macrophages. Decreased MHC II expression appeared to be mediated predominantly by increased IL-10 secretion in a para-/autocrine manner. Here, we show that the functional modulation of antigen-presenting monocytes/macrophages by apoptotic cells also influences T cell activation and function. When human peripheral blood mononuclear cells were stimulated with recall antigens in the presence of apoptotic cells, interferon gamma (IFN gamma) secretion was markedly suppressed, whereas secretion of the Th2 cytokine IL-4 was not significantly altered. Hence, apoptotic cells shift the T cell cytokine secretion pattern towards a Th2-like response. This Th2 shift can largely be prevented by neutralizing IL-10, indicating an important role of this cytokine for modulating T cell cytokine secretion patterns.
0 Communities
1 Members
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14 MeSH Terms
Prostaglandin I2 analogs inhibit proinflammatory cytokine production and T cell stimulatory function of dendritic cells.
Zhou W, Hashimoto K, Goleniewska K, O'Neal JF, Ji S, Blackwell TS, Fitzgerald GA, Egan KM, Geraci MW, Peebles RS
(2007) J Immunol 178: 702-10
MeSH Terms: Animals, B7-2 Antigen, Bone Marrow, CD40 Antigens, Cell Differentiation, Cell Proliferation, Cells, Cultured, Cyclic AMP, Cytokines, Dendritic Cells, Epoprostenol, Histocompatibility Antigens Class II, Inflammation Mediators, Lymphocyte Activation, Mice, NF-kappa B, T-Lymphocytes
Show Abstract · Added March 5, 2014
Signaling through the PGI(2) receptor (IP) has been shown to inhibit inflammatory responses in mouse models of respiratory syncytial viral infection and OVA-induced allergic responses. However, little is known about the cell types that mediate the anti-inflammatory function of PGI(2.) In this study, we determined that PGI(2) analogs modulate dendritic cell (DC) cytokine production, maturation, and function. We report that PGI(2) analogs (iloprost, cicaprost, treprostinil) differentially modulate the response of murine bone marrow-derived DC (BMDC) to LPS in an IP-dependent manner. The PGI(2) analogs decreased BMDC production of proinflammatory cytokines (IL-12, TNF-alpha, IL-1alpha, IL-6) and chemokines (MIP-1alpha, MCP-1) and increased the production of the anti-inflammatory cytokine IL-10 by BMDCs. The modulatory effect was associated with IP-dependent up-regulation of intracellular cAMP and down-regulation of NF-kappaB activity. Iloprost and cicaprost also suppressed LPS-induced expression of CD86, CD40, and MHC class II molecules by BMDCs and inhibited the ability of BMDCs to stimulate Ag-specific CD4 T cell proliferation and production of IL-5 and IL-13. These findings suggest that PGI(2) signaling through the IP may exert anti-inflammatory effects by acting on DC.
1 Communities
1 Members
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17 MeSH Terms