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What one lipid giveth, another taketh away.
Joyce S, Spiller BW, Van Kaer L
(2019) Nat Immunol 20: 1559-1561
MeSH Terms: Antigen Presentation, Humans, Inflammation, Sphingomyelins
Added March 3, 2020
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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.
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16 MeSH Terms
Anti-Insulin B Cells Are Poised for Antigen Presentation in Type 1 Diabetes.
Felton JL, Maseda D, Bonami RH, Hulbert C, Thomas JW
(2018) J Immunol 201: 861-873
MeSH Terms: Animals, Antigen Presentation, Autoantibodies, Autoantigens, B-Lymphocyte Subsets, Diabetes Mellitus, Type 1, Female, Immune Tolerance, Inflammation, Insulin, Insulin Antibodies, Lymphocyte Activation, Male, Mice, Mice, Inbred NOD, Mice, Transgenic, Receptors, Antigen, B-Cell
Show Abstract · Added July 20, 2018
Early breaches in B cell tolerance are central to type 1 diabetes progression in mouse and man. Conventional BCR transgenic mouse models (VH125.Tg NOD) reveal the power of B cell specificity to drive disease as APCs. However, in conventional fixed IgM models, comprehensive assessment of B cell development is limited. To provide more accurate insight into the developmental and functional fates of anti-insulin B cells, we generated a new NOD model (V125NOD) in which anti-insulin VDJH125 is targeted to the IgH chain locus to generate a small (1-2%) population of class switch-competent insulin-binding B cells. Tracking of this rare population in a polyclonal repertoire reveals that anti-insulin B cells are preferentially skewed into marginal zone and late transitional subsets known to have increased sensitivity to proinflammatory signals. Additionally, IL-10 production, characteristic of regulatory B cell subsets, is increased. In contrast to conventional models, class switch-competent anti-insulin B cells proliferate normally in response to mitogenic stimuli but remain functionally silent for insulin autoantibody production. Diabetes development is accelerated, which demonstrates the power of anti-insulin B cells to exacerbate disease without differentiation into Ab-forming or plasma cells. Autoreactive T cell responses in V125NOD mice are not restricted to insulin autoantigens, as evidenced by increased IFN-γ production to a broad array of diabetes-associated epitopes. Together, these results independently validate the pathogenic role of anti-insulin B cells in type 1 diabetes, underscore their diverse developmental fates, and demonstrate the pathologic potential of coupling a critical β cell specificity to predominantly proinflammatory Ag-presenting B cell subsets.
Copyright © 2018 by The American Association of Immunologists, Inc.
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17 MeSH Terms
Autophagy-related protein Vps34 controls the homeostasis and function of antigen cross-presenting CD8α dendritic cells.
Parekh VV, Pabbisetty SK, Wu L, Sebzda E, Martinez J, Zhang J, Van Kaer L
(2017) Proc Natl Acad Sci U S A 114: E6371-E6380
MeSH Terms: Animals, Antigen Presentation, Autophagy, Autophagy-Related Proteins, CD8 Antigens, CD8-Positive T-Lymphocytes, Cells, Cultured, Class III Phosphatidylinositol 3-Kinases, Cross-Priming, Cytokines, Dendritic Cells, Endocytosis, Histocompatibility Antigens Class I, Melanoma, Experimental, Membrane Proteins, Mice, Mice, Knockout, Phagocytosis
Show Abstract · Added March 26, 2019
The class III PI3K Vacuolar protein sorting 34 (Vps34) plays a role in both canonical and noncanonical autophagy, key processes that control the presentation of antigens by dendritic cells (DCs) to naive T lymphocytes. We generated DC-specific -deficient mice to assess the contribution of Vps34 to DC functions. We found that DCs from these animals have a partially activated phenotype, spontaneously produce cytokines, and exhibit enhanced activity of the classic MHC class I and class II antigen-presentation pathways. Surprisingly, these animals displayed a defect in the homeostatic maintenance of splenic CD8α DCs and in the capacity of these cells to cross-present cell corpse-associated antigens to MHC class I-restricted T cells, a property that was associated with defective expression of the T-cell Ig mucin (TIM)-4 receptor. Importantly, mice deficient in the Vps34-associated protein Rubicon, which is critical for a noncanonical form of autophagy called "Light-chain 3 (LC3)-associated phagocytosis" (LAP), lacked such defects. Finally, consistent with their defect in the cross-presentation of apoptotic cells, DC-specific -deficient animals developed increased metastases in response to challenge with B16 melanoma cells. Collectively, our studies have revealed a critical role of Vps34 in the regulation of CD8α DC homeostasis and in the capacity of these cells to process and present antigens associated with apoptotic cells to MHC class I-restricted T cells. Our findings also have important implications for the development of small-molecule inhibitors of Vps34 for therapeutic purposes.
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Proteomics show antigen presentation processes in human immune cells after AS03-H5N1 vaccination.
Galassie AC, Goll JB, Samir P, Jensen TL, Hoek KL, Howard LM, Allos TM, Niu X, Gordy LE, Creech CB, Hill H, Joyce S, Edwards KM, Link AJ
(2017) Proteomics 17:
MeSH Terms: Adjuvants, Immunologic, Antigen Presentation, B-Lymphocytes, Cells, Cultured, Humans, Influenza A Virus, H5N1 Subtype, Influenza Vaccines, Influenza, Human, Killer Cells, Natural, Monocytes, Neutrophils, Protein Interaction Maps, Proteome, Proteomics, T-Lymphocytes
Show Abstract · Added August 15, 2017
Adjuvants enhance immunity elicited by vaccines through mechanisms that are poorly understood. Using a systems biology approach, we investigated temporal protein expression changes in five primary human immune cell populations: neutrophils, monocytes, natural killer cells, T cells, and B cells after administration of either an Adjuvant System 03 adjuvanted or unadjuvanted split-virus H5N1 influenza vaccine. Monocytes demonstrated the strongest differential signal between vaccine groups. On day 3 post-vaccination, several antigen presentation-related pathways, including MHC class I-mediated antigen processing and presentation, were enriched in monocytes and neutrophils and expression of HLA class I proteins was increased in the Adjuvant System 03 group. We identified several protein families whose proteomic responses predicted seroprotective antibody responses (>1:40 hemagglutination inhibition titer), including inflammation and oxidative stress proteins at day 1 as well as immunoproteasome subunit (PSME1 and PSME2) and HLA class I proteins at day 3 in monocytes. While comparison between temporal proteomic and transcriptomic results showed little overlap overall, enrichment of the MHC class I antigen processing and presentation pathway in monocytes and neutrophils was confirmed by both approaches.
© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
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15 MeSH Terms
Cell-Based Systems Biology Analysis of Human AS03-Adjuvanted H5N1 Avian Influenza Vaccine Responses: A Phase I Randomized Controlled Trial.
Howard LM, Hoek KL, Goll JB, Samir P, Galassie A, Allos TM, Niu X, Gordy LE, Creech CB, Prasad N, Jensen TL, Hill H, Levy SE, Joyce S, Link AJ, Edwards KM
(2017) PLoS One 12: e0167488
MeSH Terms: Adjuvants, Immunologic, Adolescent, Adult, Antibodies, Viral, Antibody Formation, Antigen Presentation, Chemokine CXCL10, Dendritic Cells, Double-Blind Method, Female, Hemagglutination Inhibition Tests, Humans, Influenza A Virus, H5N1 Subtype, Influenza Vaccines, Influenza, Human, Interleukin-6, Killer Cells, Natural, Male, Middle Aged, Monocytes, Neutrophils, Systems Biology, Vaccination, Young Adult
Show Abstract · Added May 3, 2017
BACKGROUND - Vaccine development for influenza A/H5N1 is an important public health priority, but H5N1 vaccines are less immunogenic than seasonal influenza vaccines. Adjuvant System 03 (AS03) markedly enhances immune responses to H5N1 vaccine antigens, but the underlying molecular mechanisms are incompletely understood.
OBJECTIVE AND METHODS - We compared the safety (primary endpoint), immunogenicity (secondary), gene expression (tertiary) and cytokine responses (exploratory) between AS03-adjuvanted and unadjuvanted inactivated split-virus H5N1 influenza vaccines. In a double-blinded clinical trial, we randomized twenty adults aged 18-49 to receive two doses of either AS03-adjuvanted (n = 10) or unadjuvanted (n = 10) H5N1 vaccine 28 days apart. We used a systems biology approach to characterize and correlate changes in serum cytokines, antibody titers, and gene expression levels in six immune cell types at 1, 3, 7, and 28 days after the first vaccination.
RESULTS - Both vaccines were well-tolerated. Nine of 10 subjects in the adjuvanted group and 0/10 in the unadjuvanted group exhibited seroprotection (hemagglutination inhibition antibody titer > 1:40) at day 56. Within 24 hours of AS03-adjuvanted vaccination, increased serum levels of IL-6 and IP-10 were noted. Interferon signaling and antigen processing and presentation-related gene responses were induced in dendritic cells, monocytes, and neutrophils. Upregulation of MHC class II antigen presentation-related genes was seen in neutrophils. Three days after AS03-adjuvanted vaccine, upregulation of genes involved in cell cycle and division was detected in NK cells and correlated with serum levels of IP-10. Early upregulation of interferon signaling-related genes was also found to predict seroprotection 56 days after first vaccination.
CONCLUSIONS - Using this cell-based systems approach, novel mechanisms of action for AS03-adjuvanted pandemic influenza vaccination were observed.
TRIAL REGISTRATION - ClinicalTrials.gov NCT01573312.
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24 MeSH Terms
Adipocyte-specific CD1d-deficiency mitigates diet-induced obesity and insulin resistance in mice.
Satoh M, Hoshino M, Fujita K, Iizuka M, Fujii S, Clingan CS, Van Kaer L, Iwabuchi K
(2016) Sci Rep 6: 28473
MeSH Terms: 3T3-L1 Cells, Adipocytes, Adiponectin, Animals, Antigen Presentation, Antigens, CD1d, B7-1 Antigen, Diet, High-Fat, Disease Models, Animal, Disease Progression, Galactosylceramides, Insulin Resistance, Interferon-gamma, Lymphocyte Activation, Macrophage Activation, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Natural Killer T-Cells, Obesity
Show Abstract · Added July 30, 2016
It has been shown that CD1d expression and glycolipid-reactive, CD1d-restricted NKT cells exacerbate the development of obesity and insulin resistance in mice. However, the relevant CD1d-expressing cells that influence the effects of NKT cells on the progression of obesity remain incompletely defined. In this study, we have demonstrated that 3T3-L1 adipocytes can present endogenous ligands to NKT cells, leading to IFN-γ production, which in turn, stimulated 3T3-L1 adipocytes to enhance expression of CD1d and CCL2, and decrease expression of adiponectin. Furthermore, adipocyte-specific CD1d deletion decreased the size of the visceral adipose tissue mass and enhanced insulin sensitivity in mice fed a high-fat diet (HFD). Accordingly, NKT cells were less activated, IFN-γ production was significantly reduced, and levels of adiponectin were increased in these animals as compared with control mice on HFD. Importantly, macrophage recruitment into the adipose tissue of adipocyte-specific CD1d-deficient mice was significantly blunted. These findings indicate that interactions between NKT cells and CD1d-expressing adipocytes producing endogenous NKT cell ligands play a critical role in the induction of inflammation and functional modulation of adipose tissue that leads to obesity.
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21 MeSH Terms
Class-switched anti-insulin antibodies originate from unconventional antigen presentation in multiple lymphoid sites.
Wan X, Thomas JW, Unanue ER
(2016) J Exp Med 213: 967-78
MeSH Terms: Animals, Antigen Presentation, B-Lymphocytes, CD40 Antigens, Diabetes Mellitus, Type 1, Germinal Center, Immunoglobulin Class Switching, Insulin, Interleukin-4, Islets of Langerhans, Mice, Mice, Knockout, T-Lymphocytes
Show Abstract · Added November 23, 2016
Autoantibodies to insulin are a harbinger of autoimmunity in type 1 diabetes in humans and in non-obese diabetic mice. To understand the genesis of these autoantibodies, we investigated the interactions of insulin-specific T and B lymphocytes using T cell and B cell receptor transgenic mice. We found spontaneous anti-insulin germinal center (GC) formation throughout lymphoid tissues with GC B cells binding insulin. Moreover, because of the nature of the insulin epitope recognized by the T cells, it was evident that GC B cells presented a broader repertoire of insulin epitopes. Such broader recognition was reproduced by activating naive B cells ex vivo with a combination of CD40 ligand and interleukin 4. Thus, insulin immunoreactivity extends beyond the pancreatic lymph node-islets of Langerhans axis and indicates that circulating insulin, despite its very low levels, can have an influence on diabetogenesis.
© 2016 Wan et al.
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13 MeSH Terms
Extensive CD4 and CD8 T Cell Cross-Reactivity between Alphaherpesviruses.
Jing L, Laing KJ, Dong L, Russell RM, Barlow RS, Haas JG, Ramchandani MS, Johnston C, Buus S, Redwood AJ, White KD, Mallal SA, Phillips EJ, Posavad CM, Wald A, Koelle DM
(2016) J Immunol 196: 2205-2218
MeSH Terms: Alphaherpesvirinae, Antigen Presentation, Antigens, Viral, CD4-Positive T-Lymphocytes, CD8-Positive T-Lymphocytes, Cross Reactions, Cytokines, Epitopes, T-Lymphocyte, Herpesviridae Infections, Herpesvirus 1, Human, Herpesvirus 2, Human, Humans, Peptides, Receptors, Antigen, T-Cell, T-Lymphocyte Subsets, Viral Proteins
Show Abstract · Added March 30, 2020
The Alphaherpesvirinae subfamily includes HSV types 1 and 2 and the sequence-divergent pathogen varicella zoster virus (VZV). T cells, controlled by TCR and HLA molecules that tolerate limited epitope amino acid variation, might cross-react between these microbes. We show that memory PBMC expansion with either HSV or VZV enriches for CD4 T cell lines that recognize the other agent at the whole-virus, protein, and peptide levels, consistent with bidirectional cross-reactivity. HSV-specific CD4 T cells recovered from HSV-seronegative persons can be explained, in part, by such VZV cross-reactivity. HSV-1-reactive CD8 T cells also cross-react with VZV-infected cells, full-length VZV proteins, and VZV peptides, as well as kill VZV-infected dermal fibroblasts. Mono- and cross-reactive CD8 T cells use distinct TCRB CDR3 sequences. Cross-reactivity to VZV is reconstituted by cloning and expressing TCRA/TCRB receptors from T cells that are initially isolated using HSV reagents. Overall, we define 13 novel CD4 and CD8 HSV-VZV cross-reactive epitopes and strongly imply additional cross-reactive peptide sets. Viral proteins can harbor both CD4 and CD8 HSV/VZV cross-reactive epitopes. Quantitative estimates of HSV/VZV cross-reactivity for both CD4 and CD8 T cells vary from 10 to 50%. Based on these findings, we hypothesize that host herpesvirus immune history may influence the pathogenesis and clinical outcome of subsequent infections or vaccinations for related pathogens and that cross-reactive epitopes and TCRs may be useful for multi-alphaherpesvirus vaccine design and adoptive cellular therapy.
Copyright © 2016 by The American Association of Immunologists, Inc.
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Viral infection causes a shift in the self peptide repertoire presented by human MHC class I molecules.
Spencer CT, Bezbradica JS, Ramos MG, Arico CD, Conant SB, Gilchuk P, Gray JJ, Zheng M, Niu X, Hildebrand W, Link AJ, Joyce S
(2015) Proteomics Clin Appl 9: 1035-52
MeSH Terms: Amino Acid Sequence, Antigen Presentation, Cell Line, Histocompatibility Antigens Class I, Humans, Molecular Sequence Data, Oncogenes, Peptides, Proteomics, Vaccinia virus
Show Abstract · Added February 15, 2016
PURPOSE - MHC class I presentation of peptides allows T cells to survey the cytoplasmic protein milieu of host cells. During infection, presentation of self peptides is, in part, replaced by presentation of microbial peptides. However, little is known about the self peptides presented during infection, despite the fact that microbial infections alter host cell gene expression patterns and protein metabolism.
EXPERIMENTAL DESIGN - The self peptide repertoire presented by HLA-A*01;01, HLA-A*02;01, HLA-B*07;02, HLA-B*35;01, and HLA-B*45;01 (where HLA is human leukocyte antigen) was determined by tandem MS before and after vaccinia virus infection.
RESULTS - We observed a profound alteration in the self peptide repertoire with hundreds of self peptides uniquely presented after infection for which we have coined the term "self peptidome shift." The fraction of novel self peptides presented following infection varied for different HLA class I molecules. A large part (approximately 40%) of the self peptidome shift arose from peptides derived from type I interferon-inducible genes, consistent with cellular responses to viral infection. Interestingly, approximately 12% of self peptides presented after infection showed allelic variation when searched against approximately 300 human genomes.
CONCLUSION AND CLINICAL RELEVANCE - Self peptidome shift in a clinical transplant setting could result in alloreactivity by presenting new self peptides in the context of infection-induced inflammation.
© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
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10 MeSH Terms