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https://www.readbyqxmd.com/read/29155844/hypoxia-and-hypoxia-inducible-factor-hif-downregulate-antigen-presenting-mhc-class-i-molecules-limiting-tumor-cell-recognition-by-t-cells
#1
Shalini Sethumadhavan, Murillo Silva, Phaethon Philbrook, Thao Nguyen, Stephen M Hatfield, Akio Ohta, Michail V Sitkovsky
Human cancers are known to downregulate Major Histocompatibility Complex (MHC) class I expression thereby escaping recognition and rejection by anti-tumor T cells. Here we report that oxygen tension in the tumor microenvironment (TME) serves as an extrinsic cue that regulates antigen presentation by MHC class I molecules. In support of this view, hypoxia is shown to negatively regulate MHC expression in a HIF-dependent manner as evidenced by (i) lower MHC expression in the hypoxic TME in vivo and in hypoxic 3-dimensional (3D) but not 2-dimensional (2D) tumor cell cultures in vitro; (ii) decreased MHC in human renal cell carcinomas with constitutive expression of HIF due to genetic loss of von Hippel-Lindau (VHL) function as compared with isogenically paired cells with restored VHL function, and iii) increased MHC in tumor cells with siRNA-mediated knockdown of HIF...
2017: PloS One
https://www.readbyqxmd.com/read/29150562/the-role-of-mhc-e-in-t-cell-immunity-is-conserved-among-humans-rhesus-macaques-and-cynomolgus-macaques
#2
Helen L Wu, Roger W Wiseman, Colette M Hughes, Gabriela M Webb, Shaheed A Abdulhaqq, Benjamin N Bimber, Katherine B Hammond, Jason S Reed, Lina Gao, Benjamin J Burwitz, Justin M Greene, Fidel Ferrer, Alfred W Legasse, Michael K Axthelm, Byung S Park, Simon Brackenridge, Nicholas J Maness, Andrew J McMichael, Louis J Picker, David H O'Connor, Scott G Hansen, Jonah B Sacha
MHC-E is a highly conserved nonclassical MHC class Ib molecule that predominantly binds and presents MHC class Ia leader sequence-derived peptides for NK cell regulation. However, MHC-E also binds pathogen-derived peptide Ags for presentation to CD8(+) T cells. Given this role in adaptive immunity and its highly monomorphic nature in the human population, HLA-E is an attractive target for novel vaccine and immunotherapeutic modalities. Development of HLA-E-targeted therapies will require a physiologically relevant animal model that recapitulates HLA-E-restricted T cell biology...
November 17, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/29130994/enhancement-of-anti-leukemia-immunity-by-leukemia-derived-exosomes-via-downregulation-of-tgf-%C3%AE-1-expression
#3
Fang Huang, Jiangbo Wan, Weiwei Hu, Siguo Hao
BACKGROUND/AIMS: Minimal residual leukemia cells (MRLs) are difficult to eradicate through traditional treatment and therefore remain to be a major threat to the long-term survival of leukemia patients. Tumor-derived exosomes (TEXs), which carry tumor associated antigens (TAA), may be a potential cell-free tumor vaccine for the specific eradication of MRLs. However, TEXs are intended to be less immunogenic due to exosomal TGF-β1. To further optimize the efficacy of TEX-based vaccines, we investigated whether exosomes from TGF-β1 silenced leukemia cells (LEXTGF-β1si) had an increased potential to induce a specific antitumor effect compared with non-modified exosomes...
November 9, 2017: Cellular Physiology and Biochemistry
https://www.readbyqxmd.com/read/29118127/peripheral-blood-biomarkers-of-disease-outcome-in-a-monkey-model-of-rift-valley-fever-encephalitis
#4
Elizabeth R Wonderlich, Amy L Caroline, Cynthia M McMillen, Aaron W Walters, Douglas S Reed, Simon M Barratt-Boyes, Amy L Hartman
Rift Valley Fever (RVF) is an emerging arboviral disease of livestock and people. Although a mosquito-borne virus, humans are infected through contact with or inhalation of virus-laden particles from contaminated animal carcasses. Some individuals infected with RVF virus (RVFV) develop meningoencephalitis resulting in morbidity and mortality. Little is known about the pathogenic mechanisms that lead to neurologic sequelae, and thus animal models that represent human disease are needed. African green monkeys (AGM) exposed to aerosols containing RVFV develop a reproducibly lethal neurological disease that resembles human illness...
November 8, 2017: Journal of Virology
https://www.readbyqxmd.com/read/29107940/structure-of-the-human-mhc-i-peptide-loading-complex
#5
Andreas Blees, Dovile Januliene, Tommy Hofmann, Nicole Koller, Carla Schmidt, Simon Trowitzsch, Arne Moeller, Robert Tampé
The peptide-loading complex (PLC) is a transient, multisubunit membrane complex in the endoplasmic reticulum that is essential for establishing a hierarchical immune response. The PLC coordinates peptide translocation into the endoplasmic reticulum with loading and editing of major histocompatibility complex class I (MHC-I) molecules. After final proofreading in the PLC, stable peptide-MHC-I complexes are released to the cell surface to evoke a T-cell response against infected or malignant cells. Sampling of different MHC-I allomorphs requires the precise coordination of seven different subunits in a single macromolecular assembly, including the transporter associated with antigen processing (TAP1 and TAP2, jointly referred to as TAP), the oxidoreductase ERp57, the MHC-I heterodimer, and the chaperones tapasin and calreticulin...
November 6, 2017: Nature
https://www.readbyqxmd.com/read/29106333/monomethyl-fumarate-treatment-impairs-maturation-of-human-myeloid-dendritic-cells-and-their-ability-to-activate-t-cells
#6
Maria Antonietta Mazzola, Radhika Raheja, Keren Regev, Vanessa Beynon, Felipe von Glehn, Anu Paul, Isabelle Pierre, Pia Kivisakk, Howard L Weiner, Roopali Gandhi
BACKGROUND: Dimethyl fumarate (DMF) and its active metabolite monomethyl fumarate (MMF) effectively lead to reduction in disease relapses and active magnetic resonance imaging (MRI) lesions. DMF and MMF are known to be effective in modulating T- and B-cell responses; however, their effect on the phenotype and function of human myeloid dendritic cells (mDCs) is not fully understood. OBJECTIVE: To investigate the role of MMF on human mDCs maturation and function. METHODS: mDCs from healthy controls were isolated and cultured in vitro with MMF...
November 1, 2017: Multiple Sclerosis: Clinical and Laboratory Research
https://www.readbyqxmd.com/read/29106304/role-of-mait-cells-in-the-immunopathogenesis-of-inflammatory-diseases-new-players-in-old-game
#7
Vijay Kumar, Ali Ahmad
Current advances in immunology have led to the identification of a population of novel innate immune T cells, called mucosa-associated invariant T (MAIT) cells. The cells in humans express an invariant TCRα chain (Vα7.2-Jα33) paired with a limited subset of TCRβ chains (Vβ2, 13 and 22), are restricted by the MHC class I (MH1)-related (MR)-1, and recognize molecules that are produced in the bacterial riboflavin (vitamin B2) biosynthetic pathway. They are present in the circulation, liver and at various mucosal sites (i...
November 6, 2017: International Reviews of Immunology
https://www.readbyqxmd.com/read/29103682/expression-of-immunoproteasome-subunits-in-the-porcine-lung-alterations-during-normal-and-inflammatory-conditions
#8
Qiang Liu, Yong-Li Zhang, Shou-Ping Hu, Ze-Lin Ma, Su-Li Gao, Bin Sun, Fei Xiao, Zhuo Zhang, Xue-Hui Cai, Xi-Jun He
The elimination of infected cells by cytotoxic T lymphocytes (CTLs) occurs through interactions between T cell receptors (TCRs) and pathogen-derived antigenic peptide-major histocompatibility complex (MHC) class I complexes. The immunoproteasome (i-proteasome), which is a large proteolytic machine derived from the constitutive proteasome, is highly efficient at processing antigens for presentation on MHC class I molecules to activate CD8(+) T lymphocytes; this in turn facilitates antiviral adaptive immune responses...
October 2017: Veterinary Microbiology
https://www.readbyqxmd.com/read/29100330/protective-cellular-immunity-generated-by-cross-presenting-recombinant-overlapping-peptide-proteins
#9
Lili Cai, Jianbo Zhang, Renying Zhu, Weixing Shi, Xiaobing Xia, Mark Edwards, William Finch, Anthony Coombs, Ju Gao, Kangwen Chen, Sophie Owen, Shisong Jiang, Wenshu Lu
Priming of naive CD8(+) and CD4(+) T cells by dendritic cells (DCs) requires effective antigen presentation on both MHC class I and II molecules. We have developed a novel technology to use recombinant overlapping peptides (ROP) that stimulate both CD8(+) and CD4(+) T cell immune responses. The single chain protein of a ROP is made up of overlapping peptides linked by the target sequence (LRMK) for cathepsin S, a protease found in the endosomes of DCs. We designed synthetic genes encoding ROPs derived from ovalbumin (OVA), tuberculosis protein (CFP10-ESAT6), human papilloma virus (HPV) protein (E7) and survivin, a protein commonly over-expressed in tumour cells...
September 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/29092744/dual-requirement-for-stat-signaling-in-dendritic-cell-immunobiology
#10
Gloria Donninelli, Isabella Sanseverino, Cristina Purificato, Sandra Gessani, Maria Cristina Gauzzi
Dendritic cells (DC) represent an attractive target for therapeutic manipulation of the immune system and enhancement of insufficient immune response in cancer. STAT family members play key roles in the differentiation and activation of DC, a feature that is currently being exploited in DC-based therapies. We previously reported that the small-molecule Stattic, originally developed as a STAT3-specific inhibitor, also inhibits STAT1 and STAT2 phosphorylation in DC exposed to cytokines or LPS. Aim of this study was to investigate the functional consequences of in vitro treatment with Stattic on DC immunobiology...
October 27, 2017: Immunobiology
https://www.readbyqxmd.com/read/29089071/-whole-glucan-particle-promotes-the-maturation-of-tumor-educated-mouse-dendritic-cells-to-suppress-regulatory-t-cell-differentiation
#11
Yu Bai, Yongling Ning, Hong Zhou, Chunjian Qi
Objective To investigate the maturation and immune responses of tumor-educated dendritic cells (TEDCs) stimulated by whole glucan particle (WGP). Methods Mouse bone marrow-derived dendritic cells were generated by Flt3 ligand and co-cultured with interleukin 10 (IL-10) and transforming growth factor β (TGF-β) in vitro to induce TEDCs, and then stimulated by WGP for 2 days. CD4(+) FOXP3(+) T cells from the lymph nodes and spleens of OT-II mice were purified by magnetic-activated cell sorting, and then co-cultured with TEDCs in the presence of ovalbumin (OVA)...
September 2017: Xi Bao Yu Fen Zi Mian Yi Xue za Zhi, Chinese Journal of Cellular and Molecular Immunology
https://www.readbyqxmd.com/read/29075267/pd-1-controls-tonic-signaling-and-lymphopenia-induced-proliferation-of-t-lymphocytes
#12
Kristofor K Ellestad, Jiaxin Lin, Louis Boon, Colin C Anderson
Recovery of the T lymphocyte compartment within a lymphopenic host by lymphopenia-induced proliferation (LIP) is regulated by inter- and intraclonal competition for limited resources, including homeostatic cytokines and peptide:MHC (pMHC) complexes with which the TCR can interact at least weakly to yield a tonic signal. Importantly, the process of LIP can synergize with other factors that promote T cell activation to drive inflammatory disease. While reconstitution of the lymphoid compartment of immune deficient Rag(-/-) mice by transfer of wild-type hematopoietic stem cells (HSC) does not generally result in an overt disease phenotype, transfer of HSC deficient in expression of the co-inhibitory molecule PD-1 results in severe systemic autoimmunity driven by newly generated T cells that emerge from the thymus into the periphery and undergo LIP...
2017: Frontiers in Immunology
https://www.readbyqxmd.com/read/29074459/a-novel-recycling-mechanism-of-native-ige-antigen-complexes-in-human-b-cells-facilitates-transfer-of-antigen-to-dendritic-cells-for-antigen-presentation
#13
P Engeroff, M Fellmann, D Yerly, M F Bachmann, M Vogel
BACKGROUND: IgE-immune complexes have been shown to enhance antibody and T cell responses in mice by targeting CD23 (FcεRII), the low-affinity receptor for IgE on B cells. In humans, the mechanism by which CD23-expressing cells take up IgE-immune complexes (IgE-IC) and process them is not well understood. OBJECTIVE: To investigate this question, we compared the fate of IgE-IC in human B cells and in CD23 expressing monocyte-derived dendritic cells (moDCs) that represent classical APCs and we aimed at studying IgE-dependent antigen presentation in both cell types...
October 23, 2017: Journal of Allergy and Clinical Immunology
https://www.readbyqxmd.com/read/29074182/t-cell-ignorance-is-bliss-t-cells-are-not-tolerized-by-langerhans-cells-presenting-human-papillomavirus-antigens-in-the-absence-of-costimulation
#14
Andrew W Woodham, Lisa Yan, Joseph G Skeate, Daniel van der Veen, Heike E Brand, Michael K Wong, Diane M Da Silva, W Martin Kast
Human papillomavirus type 16 (HPV16) infections are intra-epithelial, and thus, HPV16 is known to interact with Langerhans cells (LCs), the resident epithelial antigen-presenting cells (APCs). The current paradigm for APC-mediated induction of T cell anergy is through delivery of T cell receptor signals via peptides on MHC molecules (signal 1), but without costimulation (signal 2). We previously demonstrated that LCs exposed to HPV16 in vitro present HPV antigens to T cells without costimulation, but it remained uncertain if such T cells would remain ignorant, become anergic, or in the case of CD4+ T cells, differentiate into Tregs...
December 2016: Papillomavirus Research
https://www.readbyqxmd.com/read/29066254/ci8-short-a-novel-lps-induced-peptide-from-the-ascidian-ciona-intestinalis-modulates-responses-of-the-human-immune-system
#15
Angela Bonura, Aiti Vizzini, Sara Vlah, Francesco Gervasi, Alessandra Longo, Mario R Melis, Frank A Schildberg, Paolo Colombo
The selective modulation of immunity is an emerging concept driven by the vast advances in our understanding of this crucial host defense system. Invertebrates have raised researchers' interest as potential sources of new bioactive molecules owing to their antibacterial, anticancer and immunomodulatory activities. A LipoPolySaccharide (LPS) challenge in the ascidian Ciona intestinalis generates the transcript, Ci8 short, with cis-regulatory elements in the 3' UTR region that are essential for shaping innate immune responses...
October 16, 2017: Immunobiology
https://www.readbyqxmd.com/read/29058602/the-crosstalk-between-autophagic-and-endo-exosomal-pathways-in-antigen-processing-for-mhc-presentation-in-anticancer-t-cell-immune-responses
#16
REVIEW
Liangshun You, Liping Mao, Juying Wei, Shenhe Jin, Chunmei Yang, Hui Liu, Li Zhu, Wenbin Qian
T cells recognize antigen fragments from proteolytic products that are presented to them in the form of peptides on major histocompatibility complex (MHC) molecules, which is crucial for the T cell to identify infected or transformed cells. Autophagy, a process that delivers cytoplasmic constituents for lysosomal degradation, has been observed to provide a substantial source of intra- and extracellular antigens for MHC presentation to T cells, which will impact the tumor-specific immune response. Meanwhile, extracellular components are transported to cytoplasm for the degradation/secretion process by the endo-/exosomal pathway and are thus involved in multiple physiological and pathological processes, including immune responses...
October 23, 2017: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/29054890/natural-killer-t-cell-immunotherapy-in-combination-with-chemotherapy-induced-immunogenic-cell-death-targets-metastatic-breast-cancer
#17
Simon Gebremeskel, Lynnea Lobert, Kaitlyn Tanner, Brynn Walker, Tora Oliphant, Livia E Clarke, Graham Dellaire, Brent Johnston
Natural killer T (NKT) cells are glycolipid-reactive lymphocytes that promote cancer control. In previous studies, NKT-cell activation improved survival and antitumor immunity in a post-surgical mouse model of metastatic breast cancer. Herein, we investigated whether NKT-cell activation could be combined with chemotherapeutic agents to augment therapeutic outcomes. Gemcitabine and cyclophosphamide analogs enhanced the potential immunogenicity of 4T1 mammary carcinoma cells by increasing the expression of antigen-presenting molecules (MHC-I, MHC-II, and CD1d) and promoting exposure or release of immunogenic cell death markers (calreticulin, HMGB1 and ATP)...
October 20, 2017: Cancer Immunology Research
https://www.readbyqxmd.com/read/29054371/ragweed-pollen-as-an-oral-vaccine-delivery-system-mechanistic-insights
#18
Md Jasim Uddin, Harvinder Singh Gill
We have recently developed pollen grains (PGs) as a unique method to deliver vaccines orally. Extensive chemical processing ensures allergen-free pollen microcapsules that can be loaded with vaccine antigens. Successful oral vaccine delivery has been previously demonstrated by us in a mouse model. However, the underlying mechanisms that help the processed PGs to achieve this goal were not fully understood. In this study, we wanted to understand the effects of chemically processed ragweed pollen (Ambrosia elatior) on the innate immune system...
October 17, 2017: Journal of Controlled Release: Official Journal of the Controlled Release Society
https://www.readbyqxmd.com/read/29054272/insights-on-the-hla-binding-peptidome-in-cancer
#19
Douglas F Lake
The intracellular compartments for proteolytic antigen processing in tumor cells produce peptides that are presented by MHC molecules to T cells. But first, the ubiquitin ligase system tags defective, misfolded, aged, and unstable proteins for degradation through the proteasome. Ubiqitinated proteins are unfolded and fed into the barrel-shaped core of the proteasome where a collection of multiple different proteases cleave proteins into oligopeptides. After exiting the proteasome, these oligopeptides are either completely degraded into amino acids or trimmed at the N- and C-termini so that they bind to transporter associated with antigen processing (TAP)...
2017: Enzymes
https://www.readbyqxmd.com/read/29052750/impact-of-a-cd4-gene-haplotype-on-the-immune-response-in-minipigs
#20
Fany Blanc, Françoise Créchet, Nicolas Bruneau, Guillaume Piton, Jean-Jacques Leplat, Fabrice Andréoletti, Giorgia Egidy, Silvia Vincent-Naulleau, Emmanuelle Bourneuf
The cluster of differentiation 4 (CD4) molecule functions as a co-receptor for MHC class II binding to TCR in T helper cells. A CD4 epitope deficiency was identified in the swine MeLiM (melanoblastoma-bearing Libechov minipig) strain, a model for spontaneous cutaneous melanoma development and regression. Extensive sequencing revealed a high genetic variability of CD4 and the existence of several haplotypes segregating in MeLiM. Forty polymorphisms were identified in the coding sequence, out of which 20 correspond to non-synonymous variants and 10 are located in the 3'UTR of CD4 transcripts...
October 20, 2017: Immunogenetics
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