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https://www.readbyqxmd.com/read/28940416/neurotransmitter-signaling-via-nmda-receptors-leads-to-decreased-th1-like-and-enhanced-th2-like-immune-balance-in-humans
#1
Kanami Orihara, Solomon O Odemuyiwa, Bill Stefura, Ramses Ilarraza, Kent T HayGlass, Redwan Moqbel
Given the pivotal roles that CD4 T cell imbalance plays in human immune disorders, much interest centres on better understanding influences that regulate human helper T cell subset dominance in vivo. Here, using primary CD4 T cells and short-term Th1 and Th2-like lines, we investigated roles and mechanisms by which neurotransmitter receptors may influence human Type 1 vs Type 2 immunity. We hypothesized N-methyl-D-aspartate receptors (NMDA-R), which play key roles in memory and learning, can also regulate human CD4+ T cell function through induction of excitotoxicity...
September 22, 2017: Immunology
https://www.readbyqxmd.com/read/28932628/a-novel-in-silico-framework-to-improve-mhc-i-epitopes-and-break-the-tolerance-to-melanoma
#2
Cristian Capasso, Aniket Magarkar, Victor Cervera-Carascon, Manlio Fusciello, Sara Feola, Martin Muller, Mariangela Garofalo, Lukasz Kuryk, Siri Tähtinen, Lucio Pastore, Alex Bunker, Vincenzo Cerullo
Tolerance toward tumor antigens, which are shared by normal tissues, have often limited the efficacy of cancer vaccines. However, wild type epitopes can be tweaked to activate cross-reactive T-cell clones, resulting in antitumor activity. The design of these analogs (i.e., heteroclitic peptides) can be difficult and time-consuming since no automated in silico tools are available. Hereby we describe the development of an in silico framework to improve the selection of heteroclitic peptides. The Epitope Discovery and Improvement System (EDIS) was first validated by studying the model antigen SIINFEKL...
2017: Oncoimmunology
https://www.readbyqxmd.com/read/28931759/combination-immunotherapy-with-tlr-agonists-and-checkpoint-inhibitors-suppresses-head-and-neck-cancer
#3
Fumi Sato-Kaneko, Shiyin Yao, Alast Ahmadi, Shannon S Zhang, Tadashi Hosoya, Megan M Kaneda, Judith A Varner, Minya Pu, Karen S Messer, Cristiana Guiducci, Robert L Coffman, Kazutaka Kitaura, Takaji Matsutani, Ryuji Suzuki, Dennis A Carson, Tomoko Hayashi, Ezra Ew Cohen
Checkpoint inhibitors have demonstrated efficacy in patients with recurrent or metastatic head and neck squamous cell carcinoma (HNSCC). However, the majority of patients do not benefit from these agents. To improve the efficacy of checkpoint inhibitors, intratumoral (i.t.) injection with innate immune activators, TLR7 and TLR9 agonists, were tested along with programmed death-1 receptor (PD-1) blockade. The combination therapy suppressed tumor growth at the primary injected and distant sites in human papillomavirus-negative (HPV-negative) SCC7 and MOC1, and HPV-positive MEER syngeneic mouse models...
September 21, 2017: JCI Insight
https://www.readbyqxmd.com/read/28930660/the-irf4-gene-regulatory-module-functions-as-a-read-write-integrator-to-dynamically-coordinate-t%C3%A2-helper-cell-fate
#4
Veena Krishnamoorthy, Sunil Kannanganat, Mark Maienschein-Cline, Sarah L Cook, Jianjun Chen, Neil Bahroos, Evelyn Sievert, Emily Corse, Anita Chong, Roger Sciammas
Transcriptional regulation during CD4(+) T cell fate decisions enables their differentiation into distinct states, guiding immune responses toward antibody production via Tfh cells or inflammation by Teff cells. Tfh-Teff cell fate commitment is regulated by mutual antagonism between the transcription factors Bcl6 and Blimp-1. Here we examined how T cell receptor (TCR) signals establish and arbitrate Bcl6-Blimp-1 counter-antagonism. We found that the TCR-signal-induced transcription factor Irf4 is essential for the differentiation of Bcl6-expressing Tfh and Blimp-1-expressing Teff cells...
September 19, 2017: Immunity
https://www.readbyqxmd.com/read/28928269/perturbed-cd8-t-cell-immunity-across-universal-influenza-epitopes-in-the-elderly
#5
Thi H O Nguyen, Sneha Sant, Nicola L Bird, Emma J Grant, E Bridie Clemens, Marios Koutsakos, Sophie A Valkenburg, Stephanie Gras, Martha Lappas, Anthony Jaworowski, Jane Crowe, Liyen Loh, Katherine Kedzierska
Influenza epidemics lead to severe illness, life-threatening complications, and deaths, especially in the elderly. As CD8(+) T cells are associated with rapid recovery from influenza, we investigated the effects of aging on antigen-specific CD8(+) T cells across the universal influenza epitopes in humans. We show that aging is characterized by altered frequencies in T cell subsets, with naive T cells being partially replaced by activated effector/memory populations. Although we observed no striking differences in TCR signaling capacity, T cells in the elderly had increased expression of transcription factors Eomes and T-bet, and such changes were most apparent in CD8(+) T cells...
September 19, 2017: Journal of Leukocyte Biology
https://www.readbyqxmd.com/read/28926770/1-25-oh-2d3-induces-regulatory-t-cell-differentiation-by-influencing-the-vdr-plc-%C3%AE-1-tgf-%C3%AE-1-pathway
#6
Qiang Zhou, Shengying Qin, Jinyan Zhang, Lin Zhon, Zhihai Pen, Tonghai Xing
Vitamin D has been recommended as an immune modulator in recent years, in addition to regulating calcium-phosphorous-bone metabolism. Clinical studies on organ transplantation found that vitamin D sufficiency patients were less likely to develop acute cellular rejection within one year after transplantation compared to those with vitamin D deficiency. Thus, a high percentage of regulatory T cells might play a key role in preventing acute cellular rejection (ACR). In this report, we studied the specific effects of 1,25(OH)2D3 on human T cell diff ;erentiation, and determined the potential molecule mechanism behind...
September 16, 2017: Molecular Immunology
https://www.readbyqxmd.com/read/28919076/mitochondrial-priming-by-cd28
#7
Ramon I Klein Geltink, David O'Sullivan, Mauro Corrado, Anna Bremser, Michael D Buck, Joerg M Buescher, Elke Firat, Xuekai Zhu, Gabriele Niedermann, George Caputa, Beth Kelly, Ursula Warthorst, Anne Rensing-Ehl, Ryan L Kyle, Lana Vandersarren, Jonathan D Curtis, Annette E Patterson, Simon Lawless, Katarzyna Grzes, Jing Qiu, David E Sanin, Oliver Kretz, Tobias B Huber, Sophie Janssens, Bart N Lambrecht, Angelika S Rambold, Edward J Pearce, Erika L Pearce
T cell receptor (TCR) signaling without CD28 can elicit primary effector T cells, but memory T cells generated during this process are anergic, failing to respond to secondary antigen exposure. We show that, upon T cell activation, CD28 transiently promotes expression of carnitine palmitoyltransferase 1a (Cpt1a), an enzyme that facilitates mitochondrial fatty acid oxidation (FAO), before the first cell division, coinciding with mitochondrial elongation and enhanced spare respiratory capacity (SRC). microRNA-33 (miR33), a target of thioredoxin-interacting protein (TXNIP), attenuates Cpt1a expression in the absence of CD28, resulting in cells that thereafter are metabolically compromised during reactivation or periods of increased bioenergetic demand...
September 1, 2017: Cell
https://www.readbyqxmd.com/read/28904128/integration-of-kinase-and-calcium-signaling-at-the-level-of-chromatin-underlies-inducible-gene-activation-in-t-cells
#8
Ruth Brignall, Pierre Cauchy, Sarah L Bevington, Bethany Gorman, Angela O Pisco, James Bagnall, Christopher Boddington, William Rowe, Hazel England, Kevin Rich, Lorraine Schmidt, Nigel P Dyer, Mark A Travis, Sascha Ott, Dean A Jackson, Peter N Cockerill, Pawel Paszek
TCR signaling pathways cooperate to activate the inducible transcription factors NF-κB, NFAT, and AP-1. In this study, using the calcium ionophore ionomycin and/or PMA on Jurkat T cells, we show that the gene expression program associated with activation of TCR signaling is closely related to specific chromatin landscapes. We find that calcium and kinase signaling cooperate to induce chromatin remodeling at ∼2100 chromatin regions, which demonstrate enriched binding motifs for inducible factors and correlate with target gene expression...
September 13, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28902773/reduced-tcr-signalling-contributes-to-impaired-th17-responses-in-tolerant-kidney-transplant-recipients
#9
Estefania Nova-Lamperti, Marco Romano, Sofia Christakoudi, Manohursingh Runglall, Reuben McGregor, Paula Mobillo, Yogesh Kamra, Tjir-Li Tsui, Sonia Norris, Susan John, Dominic A Boardman, Robert I Lechler, Giovanna Lombardi, Maria P Hernandez-Fuentes
BACKGROUND: The development of spontaneous kidney transplant tolerance has been associated with numerous B cell-related immune alterations. We have previously shown that tolerant recipients exhibit reduced B cell receptor (BCR) signalling and higher IL-10 production than healthy volunteers. However, it is unclear whether CD4T cells from tolerant recipients also display an antiinflammatory profile that could contribute to graft maintenance. METHODS: CD4T cells were isolated from kidney transplant recipients who were identified as being tolerant recipients, patients with chronic-rejection or healthy volunteers...
September 12, 2017: Transplantation
https://www.readbyqxmd.com/read/28900926/immunological-disorders-regulation-of-ca-2-signaling-in-t-lymphocytes
#10
Sonal Srikanth, Jin Seok Woo, Zuoming Sun, Yousang Gwack
Engagement of T cell receptors (TCRs) with cognate antigens triggers cascades of signaling pathways in helper T cells. TCR signaling is essential for the effector function of helper T cells including proliferation, differentiation, and cytokine production. It also modulates effector T cell fate by inducing cell death, anergy (nonresponsiveness), exhaustion, and generation of regulatory T cells. One of the main axes of TCR signaling is the Ca(2+)-calcineurin-nuclear factor of activated T cells (NFAT) signaling pathway...
2017: Advances in Experimental Medicine and Biology
https://www.readbyqxmd.com/read/28900678/socs1-regulator-of-t-cells-in-autoimmunity-and-cancer
#11
Subburaj Ilangumaran, Diwakar Bobbala, Sheela Ramanathan
SOCS1 is a negative feedback regulator of cytokine and growth factor receptor signaling, and plays an indispensable role in attenuating interferon gamma signaling. Studies on SOCS1-deficient mice have established a crucial role for SOCS1 in regulating CD8(+) T cell homeostasis. In the thymus, SOCS1 prevents thymocytes that had failed positive selection from surviving and expanding, ensures negative selection and prevents inappropriate developmental skewing toward the CD8 lineage. In the periphery, SOCS1 not only controls production of T cell stimulatory cytokines but also attenuates the sensitivity of CD8(+) T cells to synergistic cytokine stimulation and antigen non-specific activation...
September 13, 2017: Current Topics in Microbiology and Immunology
https://www.readbyqxmd.com/read/28893902/the-cytosolic-domain-of-t-cell-receptor-%C3%AE-associates-with-membranes-in-a-dynamic-equilibrium-and-deeply-penetrates-the-bilayer
#12
Kerstin Zimmermann, Rebecca Eells, Frank Heinrich, Stefanie Rintoul, Brian Josey, Prabhanshu Shekhar, Mathias Lösche, Lawrence J Stern
Interactions between lipid bilayers and the membrane-proximal regions of membrane-associated proteins play important roles in regulat-ing membrane protein structure and function. The T-cell antigen receptor (TCR) is an assembly of eight single-pass membrane-spanning subunits on the surface of T-lymphocytes that initiates cytosolic signaling cascades upon binding antigens presented by MHC-family proteins on antigen-presenting cells. Its ζ subunit contains multiple cytosolic immunoreceptor tyrosine-based activation motifs (ITAMs) involved in signal transduction, and this subunit by itself is sufficient to couple extracellular stimuli to intracellular signaling events...
September 11, 2017: Journal of Biological Chemistry
https://www.readbyqxmd.com/read/28891065/il4-induced-gene-1-is-secreted-at-the-immune-synapse-and-modulates-tcr-activation-independently-of-its-enzymatic-activity
#13
Aude Aubatin, Nouhoum Sako, Xavier Decrouy, Emmanuel Donnadieu, Valérie Molinier-Frenkel, Flavia Castellano
Amino-acid catabolizing enzymes produced by mononuclear phagocytes play a central role in regulating the immune response. The mammalian phenylalanine-catabolizing enzyme IL4-induced gene 1 (IL4I1) inhibits effector T lymphocyte proliferation and facilitates regulatory T-cell development. IL4I1 expression by macrophages of various human tumors may affect patient prognosis as it facilitates tumor escape from the T-cell response in murine models. Its enzymatic activity appears to participate in its effects, but some actions of IL4I1 remain unclear...
September 10, 2017: European Journal of Immunology
https://www.readbyqxmd.com/read/28889989/the-tnf-receptor-superfamily-nf-%C3%AE%C2%BAb-axis-is-critical-to-maintain-effector-regulatory-t-cells-in-lymphoid-and-non-lymphoid-tissues
#14
Ajithkumar Vasanthakumar, Yang Liao, Peggy Teh, Maria F Pascutti, Anna E Oja, Alexandra L Garnham, Renee Gloury, Jessica C Tempany, Tom Sidwell, Eloy Cuadrado, Paul Tuijnenburg, Taco W Kuijpers, Najoua Lalaoui, Lisa A Mielke, Vanessa L Bryant, Philip D Hodgkin, John Silke, Gordon K Smyth, Martijn A Nolte, Wei Shi, Axel Kallies
After exiting the thymus, Foxp3(+) regulatory T (Treg) cells undergo further differentiation in the periphery, resulting in the generation of mature, fully suppressive effector (e)Treg cells in a process dependent on TCR signaling and the transcription factor IRF4. Here, we show that tumor necrosis factor receptor superfamily (TNFRSF) signaling plays a crucial role in the development and maintenance of eTreg cells. TNFRSF signaling activated the NF-κB transcription factor RelA, which was required to maintain eTreg cells in lymphoid and non-lymphoid tissues, including RORγt(+) Treg cells in the small intestine...
September 19, 2017: Cell Reports
https://www.readbyqxmd.com/read/28889947/an-nf-%C3%AE%C2%BAb-transcription-factor-dependent-lineage-specific-transcriptional-program-promotes-regulatory-t-cell-identity-and-function
#15
Hyunju Oh, Yenkel Grinberg-Bleyer, Will Liao, Dillon Maloney, Pingzhang Wang, Zikai Wu, Jiguang Wang, Dev M Bhatt, Nicole Heise, Roland M Schmid, Matthew S Hayden, Ulf Klein, Raul Rabadan, Sankar Ghosh
Both conventional T (Tconv) cells and regulatory T (Treg) cells are activated through ligation of the T cell receptor (TCR) complex, leading to the induction of the transcription factor NF-κB. In Tconv cells, NF-κB regulates expression of genes essential for T cell activation, proliferation, and function. However the role of NF-κB in Treg function remains unclear. We conditionally deleted canonical NF-κB members p65 and c-Rel in developing and mature Treg cells and found they have unique but partially redundant roles...
September 19, 2017: Immunity
https://www.readbyqxmd.com/read/28888033/modulation-of-%C3%AE-%C3%AE-t-cell-activation-by-neutrophil-elastase
#16
Nadia Yasmín Towstyka, Carolina Maiumi Shiromizu, Irene Keitelman, Florencia Sabbione, Gabriela Verónica Salamone, Jorge Raúl Geffner, Analía Silvina Trevani, Carolina Cristina Jancic
γδ T cells are non-conventional, innate-like T cells, characterized by a restricted TCR repertoire. They participate in protective immunity response against extracellular and intracellular pathogens, tumor surveillance, modulation of innate and adaptive immune responses, tissue healing, epithelial cell maintenance, and regulation of physiological organ function. In this study, we investigated the role of neutrophils during the activation of human blood γδ T cells through CD3 molecules. We found that the up-regulation of CD69 expression, and the production of IFN-γ and TNF-α induced by anti-CD3 antibodies were potentiated by neutrophils...
September 9, 2017: Immunology
https://www.readbyqxmd.com/read/28887429/nfm-cross-reactivity-to-mog-does-not-expand-a-critical-threshold-level-of-high-affinity-t-cells-necessary-for-onset-of-demyelinating-disease
#17
Lori Blanchfield, Joseph J Sabatino, Laurel Lawrence, Brian D Evavold
Of interest to the etiology of demyelinating autoimmune disease is the potential to aberrantly activate CD4(+) T cells due to cross-recognition of multiple self-epitopes such as has been suggested for myelin oligodendrocyte glycoprotein epitope 35-55 (MOG35-55) and neurofilament medium protein epitope 15-35 (NFM15-35). NFM15-35 is immunogenic in C57BL/6 mice but fails to induce demyelinating disease by polyclonal T cells despite having the same TCR contact residues as MOG35-55, a known encephalitogenic Ag...
September 8, 2017: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/28881401/generation-of-t-follicular-helper-cells-in-vitro-requirement-for-bcr-cross-linking-and-cognate-b-and-t-cell-interaction
#18
Anne Kolenbrander, Bastian Grewe, David Nemazee, Klaus Überla, Vladimir Temchura
The minimal requirements for in vitro modeling of the natural CD4(+) T-cell differentiation into T follicular helper (TFH) cells are still under investigation. We co-cultured wild type and TCR-transgenic CD4(+) T-cells from naïve mice with dendritic cells and BCR-transgenic B-cells in the presence of HIV-derived virus-like particles containing matched B- and T-cell epitopes. This co-culturing induced co-expression of TFH-master regulator transcription factor BCL-6 and CXCR5 in up to 10% of the wild type and up to 40% of the TCR-transgenic CD4(+) T-cells...
September 7, 2017: Immunology
https://www.readbyqxmd.com/read/28878738/overlooked-mechanisms-in-type-1-diabetes-etiology-how-unique-costimulatory-molecules-contribute-to-diabetogenesis
#19
REVIEW
David H Wagner
Type 1 Diabetes (T1D) develops when immune cells invade the pancreatic islets resulting in loss of insulin production in beta cells. T cells have been proven to be central players in that process. What is surprising, however, is that classic mechanisms of tolerance cannot explain diabetogenesis; alternate mechanisms must now be considered. T cell receptor (TCR) revision is the process whereby T cells in the periphery alter TCR expression, outside the safety-net of thymic selection pressures. This process results in an expanded T cell repertoire, capable of responding to a universe of pathogens, but limitations are that increased risk for autoimmune disease development occurs...
2017: Frontiers in Endocrinology
https://www.readbyqxmd.com/read/28878121/a-tcr%C3%AE-framework-centered-codon-shapes-a-biased-t-cell-repertoire-through-direct-mhc-and-cdr3%C3%AE-interactions
#20
Kristin Støen Gunnarsen, Lene Støkken Høydahl, Louise Fremgaard Risnes, Shiva Dahal-Koirala, Ralf Stefan Neumann, Elin Bergseng, Terje Frigstad, Rahel Frick, M Fleur du Pré, Bjørn Dalhus, Knut Ea Lundin, Shuo-Wang Qiao, Ludvig M Sollid, Inger Sandlie, Geir Åge Løset
Selection of biased T cell receptor (TCR) repertoires across individuals is seen in both infectious diseases and autoimmunity, but the underlying molecular basis leading to these shared repertoires remains unclear. Celiac disease (CD) occurs primarily in HLA-DQ2.5+ individuals and is characterized by a CD4+ T cell response against gluten epitopes dominated by DQ2.5-glia-α1a and DQ2.5-glia-α2. The DQ2.5-glia-α2 response recruits a highly biased TCR repertoire composed of TRAV26-1 paired with TRBV7-2 harboring a semipublic CDR3β loop...
September 7, 2017: JCI Insight
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