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https://www.readbyqxmd.com/read/29782203/extracellular-vesicles-extracted-from-young-donor-serum-attenuate-inflammaging-via-partially-rejuvenating-aged-t-cell-immunotolerance
#1
Weikan Wang, Liefeng Wang, Linhui Ruan, Jiyoung Oh, Xiaowei Dong, Qichuan Zhuge, Dong-Ming Su
Biologic aging results in a chronic inflammatory condition, termed inflammaging, which establishes a risk for such age-related diseases as neurocardiovascular diseases; therefore, it is of great importance to develop rejuvenation strategies that are able to attenuate inflammaging as a means of intervention for age-related diseases. A promising rejuvenation factor that is present in young blood has been found that can make aged neurons younger; however, the component in the young blood and its mechanism of action are poorly elucidated...
May 21, 2018: FASEB Journal: Official Publication of the Federation of American Societies for Experimental Biology
https://www.readbyqxmd.com/read/29776088/how-nonuniform-contact-profiles-of-t-cell-receptors-modulate-thymic-selection-outcomes
#2
Hanrong Chen, Arup K Chakraborty, Mehran Kardar
T cell receptors (TCRs) bind foreign or self-peptides attached to major histocompatibility complex (MHC) molecules, and the strength of this interaction determines T cell activation. Optimizing the ability of T cells to recognize a diversity of foreign peptides yet be tolerant of self-peptides is crucial for the adaptive immune system to properly function. This is achieved by selection of T cells in the thymus, where immature T cells expressing unique, stochastically generated TCRs interact with a large number of self-peptide-MHC; if a TCR does not bind strongly enough to any self-peptide-MHC, or too strongly with at least one self-peptide-MHC, the T cell dies...
March 2018: Physical Review. E
https://www.readbyqxmd.com/read/29775092/a-prospective-multi-centre-us-clinical-trial-to-determine-accuracy-of-febridx-point-of-care-testing-for-acute-upper-respiratory-infections-with-and-without-a-confirmed-fever
#3
Nathan I Shapiro, Wesley H Self, Jeffrey Rosen, Stephan C Sharp, Michael R Filbin, Peter C Hou, Amisha D Parekh, Michael C Kurz, Robert Sambursky
BACKGROUND: FebriDx is a 10-minute disposable point-of-care test designed to identify clinically significant systemic host immune responses and aid in the differentiation of bacterial and viral respiratory infection by simultaneously detecting C-reactive protein (CRP) and myxovirus resistance protein A (MxA) from a fingerstick blood sample. FebriDx diagnostic accuracy was evaluated in the emergency room and urgent care setting. METHODS: A prospective, multicentre, observational cohort study of acute upper respiratory tract infections (URIs), with and without a confirmed fever at the time of enrolment, was performed to evaluate the diagnostic accuracy of FebriDx to identify clinically significant bacterial infection with host response and acute pathogenic viral infection...
May 18, 2018: Annals of Medicine
https://www.readbyqxmd.com/read/29764164/immunoregulatory-antigens-novel-targets-for-cancer-immunotherapy
#4
Ayako Wakatsuki Pedersen, Katharina L Kopp, Mads Hald Andersen, Mai-Britt Zocca
Historically, the development of cancer vaccines has focused on the central role of tumor antigens in eliciting tumor-specific immune responses, with limited success. Recent advances with checkpoint blockade approaches have brought about a renewed appreciation of the importance of targeting immune suppression in cancer patients. Here we discuss a novel approach to cancer immunotherapy, namely to target recently described T cells that uniquely control cells with immune suppressive functions. Accumulating evidence support the existence of self-reactive T cells that are specific to antigens derived from immunoregulatory proteins ("immunoregulatory antigens"), such as indoleamine 2,3-dioxygenase (IDO) and PD-L1...
April 2018: Chinese Clinical Oncology
https://www.readbyqxmd.com/read/29757907/t-follicular-regulatory-cells-and-antibody-responses-in-transplantation
#5
E F Wallin
De novo donor specific antibody (DSA) formation is a major problem in transplantation, and associated with long-term graft decline and loss as well as sensitisation, limiting future transplant options. Forming high-affinity, long-lived antibody responses involves a process called the germinal center (GC) reaction, and requires interaction between several cell types, including GC B cells, T follicular helper (Tfh) and T follicular regulatory (Tfr) cells. Tfr cells are an essential component of the GC reaction, limiting its size and reducing nonspecific or self-reactive responses...
May 1, 2018: Transplantation
https://www.readbyqxmd.com/read/29755478/the-contribution-of-autoantibodies-to-inflammatory-cardiovascular-pathology
#6
REVIEW
Lee A Meier, Bryce A Binstadt
Chronic inflammation and resulting tissue damage underlie the vast majority of acquired cardiovascular disease (CVD), a general term encompassing a widely diverse array of conditions. Both innate and adaptive immune mechanisms contribute to chronic inflammation in CVD. Although maladies, such as atherosclerosis and cardiac fibrosis, are commonly conceptualized as disorders of inflammation, the cellular and molecular mechanisms that promote inflammation during the natural history of these diseases in human patients are not fully defined...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29752423/strong-homeostatic-tcr-signals-induce-formation-of-self-tolerant-virtual-memory-cd8-t-cells
#7
Ales Drobek, Alena Moudra, Daniel Mueller, Martina Huranova, Veronika Horkova, Michaela Pribikova, Robert Ivanek, Susanne Oberle, Dietmar Zehn, Kathy D McCoy, Peter Draber, Ondrej Stepanek
Virtual memory T cells are foreign antigen-inexperienced T cells that have acquired memory-like phenotype and constitute 10-20% of all peripheral CD8+ T cells in mice. Their origin, biological roles, and relationship to naïve and foreign antigen-experienced memory T cells are incompletely understood. By analyzing T-cell receptor repertoires and using retrogenic monoclonal T-cell populations, we demonstrate that the virtual memory T-cell formation is a so far unappreciated cell fate decision checkpoint. We describe two molecular mechanisms driving the formation of virtual memory T cells...
May 11, 2018: EMBO Journal
https://www.readbyqxmd.com/read/29734356/microbiota-epitope-similarity-either-dampens-or-enhances-the-immunogenicity-of-disease-associated-antigenic-epitopes
#8
Sebastian Carrasco Pro, Cecilia S Lindestam Arlehamn, Sandeep K Dhanda, Chelsea Carpenter, Mikaela Lindvall, Ali A Faruqi, Clark A Santee, Harald Renz, John Sidney, Bjoern Peters, Alessandro Sette
The microbiome influences adaptive immunity and molecular mimicry influences T cell reactivity. Here, we evaluated whether the sequence similarity of various antigens to the microbiota dampens or increases immunogenicity of T cell epitopes. Sets of epitopes and control sequences derived from 38 antigenic categories (infectious pathogens, allergens, autoantigens) were retrieved from the Immune Epitope Database (IEDB). Their similarity to microbiome sequences was calculated using the BLOSUM62 matrix. We found that sequence similarity was associated with either dampened (tolerogenic; e...
2018: PloS One
https://www.readbyqxmd.com/read/29728642/a-model-of-th17-associated-ileal-hyperplasia-that-requires-both-il-17a-and-ifn%C3%AE-to-generate-self-tolerance-and-prevent-colitis
#9
Jonathan C Jeschke, Christopher G Mayne, Jennifer Ziegelbauer, Christopher L DeCiantis, Selina Singh, Suresh N Kumar, Mariko Suchi, Yoichiro Iwakura, William R Drobyski, Nita H Salzman, Calvin B Williams
Homeostasis in the ileum, which is commonly disrupted in patients with Crohn's disease, involves ongoing immune responses. To study how homeostatic processes of the ileum impact CD4+ T cell responses, we used TCR transgenic tools to breed mice that spontaneously produced CD4+ T cells reactive to an antigen expressed in the ileum. At an early age, the ilea of these mice exhibit crypt hyperplasia and accumulate increased numbers of TH 17 cells bearing non-transgenic clonotypes. Half of these mice subsequently developed colitis linked to broad mucosal infiltration by TH 17 and TH 1 cells expressing non-transgenic clonotypes, chronic wasting disease and loss of ileal crypt hyperplasia...
May 4, 2018: Mucosal Immunology
https://www.readbyqxmd.com/read/29726044/%C3%AE-%C3%AE-t-cell-receptors-with-a-central-cdr3-cysteine-are-enriched-in-cd8%C3%AE-%C3%AE-intraepithelial-lymphocytes-and-their-thymic-precursors
#10
Rushika C Wirasinha, Mandeep Singh, Stuart K Archer, Anna Chan, Paul F Harrison, Christopher C Goodnow, Stephen R Daley
The thymus plays a crucial role in immune tolerance by exposing developing T cells (thymocytes) to a myriad of self-antigens. Strong T-cell receptor (TCR) engagement induces tolerance in self-reactive thymocytes by stimulating apoptosis or selection into specialized T-cell lineages, including intestinal TCRαβ+ CD8αα+ intraepithelial lymphocytes (IEL). TCR-intrinsic amino acid motifs that can be used to predict whether a TCR will be strongly self-reactive remain elusive. Here, a novel TCR sequence alignment approach revealed that T-cell lineages in C57BL/6 mice had divergent usage of cysteine within two positions of the amino acid at the apex of the complementarity-determining region 3 (CDR3) of the TCRα or TCRβ chain...
May 3, 2018: Immunology and Cell Biology
https://www.readbyqxmd.com/read/29724812/usp11-enhances-tgf-946-induced-epithelial-mesenchymal-plasticity-and-human-breast-cancer-metastasis
#11
Daniel A Garcia, Christina Baek, M Valeria Estrada, Tiffani Tysl, Eric J Bennett, Jing Yang, John T Chang
Epithelial-mesenchymal transition (EMT) is a conserved cellular plasticity program that is reactivated in carcinoma cells and drives metastasis. While EMT is well studied its regulatory mechanisms remain unclear. Therefore, to identify novel regulators of EMT, a data mining approach was taken using published microarray data and a group of deubiquitinases (DUBs) were found to be upregulated in cells that have undergone EMT. Here, it is demonstrated that one DUB, ubiquitin specific peptidase 11 (USP11), enhances TGFβ-induced EMT and self-renewal in immortalized human mammary epithelial cells...
May 3, 2018: Molecular Cancer Research: MCR
https://www.readbyqxmd.com/read/29721072/glucocorticoids-inhibit-oncogenic-runx1-eto-in-acute-myeloid-leukemia-with-chromosome-translocation-t-8-21
#12
Lianghao Lu, Yefei Wen, Yuan Yao, Fengju Chen, Guohui Wang, Fangrui Wu, Jingyu Wu, Padmini Narayanan, Michele Redell, Qianxing Mo, Yongcheng Song
Acute myeloid leukemia (AML) is a major blood cancer with poor prognosis. New therapies are needed to target oncogene-driven leukemia stem cells, which account for relapse and resistance. Chromosome translocation t(8;21), which produces RUNX1-ETO (R-E) fusion oncoprotein, is found in ~13% AML. R-E dominance negatively inhibits global gene expression regulated by RUNX1, a master transcription factor for hematopoiesis, causing increased self-renewal and blocked cell differentiation of hematopoietic progenitor cells, and eventually leukemia initiation...
2018: Theranostics
https://www.readbyqxmd.com/read/29707696/clonal-bifurcation-of-foxp3-expression-visualized-in-thymocytes-and-t-cells
#13
Bonnie Yen, Katherine T Fortson, Nyanza J Rothman, Nicholas Arpaia, Steven L Reiner
Regulatory T cells (Tregs) are crucial for suppressing autoimmunity and inflammation mediated by conventional T cells. To be useful, some Tregs should have overlapping specificity with relevant self-reactive or pathogen-specific clones. Whether matching recognition between Tregs and non-Tregs might arise through stochastic or deterministic mechanisms has not been addressed. We tested the hypothesis that some Tregs that arise in the thymus or that are induced during Ag-driven expansion of conventional CD4+ T cells might be clonally related to non-Tregs by virtue of asymmetric Foxp3 induction during cell division...
April 1, 2018: ImmunoHorizons
https://www.readbyqxmd.com/read/29677240/uveal-effusion-after-immune-checkpoint-inhibitor-therapy
#14
Merina Thomas, Stephen T Armenti, M Bernadete Ayres, Hakan Demirci
Importance: Immune checkpoint inhibitors, including antiprogrammed cell death protein-1 (anti-PD-1) and antiprogrammed cell death ligand-1 (anti-PD-L1) monoclonal antibodies, have recently been introduced as a promising new immunotherapy for solid cancers. The adverse effects typically include inflammation of the skin, endocrine, and gastrointestinal systems. Objective: To describe 3 patients who developed uveal effusion after initiating anti-PD-1 and anti-PD-L1 monoclonal antibody therapy...
April 12, 2018: JAMA Ophthalmology
https://www.readbyqxmd.com/read/29651165/the-mitochondrial-citrate-carrier-slc25a1-drives-stemness-and-therapy-resistance-in-non-small-cell-lung-cancer
#15
Harvey R Fernandez, Shreyas M Gadre, Mingjun Tan, Garrett T Graham, Rami Mosaoa, Martin S Ongkeko, Kyu Ah Kim, Rebecca B Riggins, Erika Parasido, Iacopo Petrini, Simone Pacini, Amrita Cheema, Rency Varghese, Habtom W Ressom, Yuwen Zhang, Christopher Albanese, Aykut Üren, Mikell Paige, Giuseppe Giaccone, Maria Laura Avantaggiati
Therapy resistance represents a clinical challenge for advanced non-small cell lung cancer (NSCLC), which still remains an incurable disease. There is growing evidence that cancer-initiating or cancer stem cells (CSCs) provide a reservoir of slow-growing dormant populations of cells with tumor-initiating and unlimited self-renewal ability that are left behind by conventional therapies reigniting post-therapy relapse and metastatic dissemination. The metabolic pathways required for the expansion of CSCs are incompletely defined, but their understanding will likely open new therapeutic opportunities...
April 12, 2018: Cell Death and Differentiation
https://www.readbyqxmd.com/read/29650674/germinal-center-antibody-mutation-trajectories-are-determined-by-rapid-self-foreign-discrimination
#16
Deborah L Burnett, David B Langley, Peter Schofield, Jana R Hermes, Tyani D Chan, Jennifer Jackson, Katherine Bourne, Joanne H Reed, Kate Patterson, Benjamin T Porebski, Robert Brink, Daniel Christ, Christopher C Goodnow
Antibodies have the specificity to differentiate foreign antigens that mimic self antigens, but it remains unclear how such specificity is acquired. In a mouse model, we generated B cells displaying an antibody that cross-reacts with two related protein antigens expressed on self versus foreign cells. B cell anergy was imposed by self antigen but reversed upon challenge with high-density foreign antigen, leading to germinal center recruitment and antibody gene hypermutation. Single-cell analysis detected rapid selection for mutations that decrease self affinity and slower selection for epistatic mutations that specifically increase foreign affinity...
April 13, 2018: Science
https://www.readbyqxmd.com/read/29618523/tuning-t-cell-signaling-sensitivity-alters-the-behavior-of-cd4-t-cells-during-an-immune-response
#17
Ashley A Viehmann Milam, Juliet M Bartleson, David L Donermeyer, Stephen Horvath, Vivek Durai, Saravanan Raju, Haiyang Yu, Veronika Redmann, Bernd Zinselmeyer, J Michael White, Kenneth M Murphy, Paul M Allen
Intricate processes in the thymus and periphery help curb the development and activation of autoreactive T cells. The subtle signals that govern these processes are an area of great interest, but tuning TCR sensitivity for the purpose of affecting T cell behavior remains technically challenging. Previously, our laboratory described the derivation of two TCR-transgenic CD4 T cell mouse lines, LLO56 and LLO118, which recognize the same cognate Listeria epitope with the same affinity. Despite the similarity of the two TCRs, LLO56 cells respond poorly in a primary infection whereas LLO118 cells respond robustly...
April 4, 2018: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/29617057/antigen-specific-helios-neuropilin-1-tregs-induce-apoptosis-of-autoreactive-b-cells-via-pd-l1
#18
Janine Gotot, Ermanila Dhana, Hideo Yagita, Romina Kaiser, Isis Ludwig-Portugall, Christian Kurts
Regulatory T cells (Tregs) maintain self-tolerance and prevent autoimmunity by controlling autoreactive T cells. We recently demonstrated in vivo that Tregs can directly suppress auto-reactive B cells via programmed death ligand 1 (PD-L1) that ligated PD-1 on B cells and caused them to undergo apoptosis. Here we asked whether this mechanism is utilized by thymus-derived natural Tregs and/or by peripheral lymphoid tissue-induced Tregs. We first demonstrated that antigen-specific PD-L1-expressing Tregs were induced in the draining lymph node (LN) of autoantigen-expressing tissue and characterized them by their lack of the transcription factor Helios and of the surface marker Neuropilin-1 (Nrp-1)...
April 4, 2018: Immunology and Cell Biology
https://www.readbyqxmd.com/read/29616017/phenotypic-and-functional-changes-of-peripheral-ly6c-t-regulatory-cells-driven-by-conventional-effector-t-cells
#19
Jun Young Lee, Juhee Kim, Jaeu Yi, Daeun Kim, Hee-Ok Kim, Daehee Han, Jonathan Sprent, You Jeong Lee, Charles D Surh, Jae-Ho Cho
A relatively high affinity/avidity of T cell receptor (TCR) recognition for self-peptide bound to major histocompatibility complex II (self-pMHC) ligands is a distinctive feature of CD4 T regulatory (Treg) cells, including their development in the thymus and maintenance of their suppressive functions in the periphery. Despite such high self-reactivity, however, all thymic-derived peripheral Treg populations are neither homogenous in their phenotype nor uniformly immune-suppressive in their function under steady state condition...
2018: Frontiers in Immunology
https://www.readbyqxmd.com/read/29596939/immune-checkpoint-blockade-therapy
#20
EDITORIAL
Thomas Wieder, Thomas Eigentler, Ellen Brenner, Dipl Biol, Martin Röcken
Immune checkpoints are accessory molecules that either promote or inhibit T cell activation. Two inhibitory molecules, cytotoxic T cell antigen 4 (CTLA-4) and programmed death 1 (PD-1), got high attention, as inhibition of CTLA-4 or PD-1 signaling provides the first immune therapy that significantly improves the survival of patients with metastatic solid cancers. Inhibition of CTLA-4 or PD-1 was first studied in and approved for patients with metastatic melanoma. Blocking immune checkpoints is also efficient in non-small-cell lung cancer, renal cell cancers, hypermutated gastro-intestinal cancers and others...
March 26, 2018: Journal of Allergy and Clinical Immunology
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