• MeSH
• CD8-pozitivní T-lymfocyty cytologie   imunologie   MeSH
• cytotoxické T-lymfocyty * MeSH
• exprese genu MeSH
• HIV infekce imunologie   MeSH
• HIV * imunologie   patogenita   MeSH
• inhibitory kontrolních bodů * analýza   MeSH
• klinické zkoušky jako téma MeSH
• lidé MeSH
• poměr CD4 a CD8 lymfocytů MeSH
• průtoková cytometrie MeSH
• stanovení celkové genové exprese MeSH
• Check Tag
• lidé MeSH

CD4 and CD8 mark helper and cytotoxic T cell lineages, respectively, and serve as coreceptors for MHC-restricted TCR recognition. How coreceptor expression is matched with TCR specificity is central to understanding CD4/CD8 lineage choice, but visualising coreceptor gene activity in individual selection intermediates has been technically challenging. It therefore remains unclear whether the sequence of coreceptor gene expression in selection intermediates follows a stereotypic pattern, or is responsive to signaling. Here we use single cell RNA sequencing (scRNA-seq) to classify mouse thymocyte selection intermediates by coreceptor gene expression. In the unperturbed thymus, Cd4+Cd8a- selection intermediates appear before Cd4-Cd8a+ selection intermediates, but the timing of these subsets is flexible according to the strength of TCR signals. Our data show that selection intermediates discriminate MHC class prior to the loss of coreceptor expression and suggest a model where signal strength informs the timing of coreceptor gene activity and ultimately CD4/CD8 lineage choice.

• MeSH
• aktivace lymfocytů genetika   MeSH
• analýza hlavních komponent MeSH
• buněčná diferenciace imunologie   MeSH
• buněčný rodokmen imunologie   MeSH
• CD4-pozitivní T-lymfocyty cytologie   imunologie   MeSH
• CD8-pozitivní T-lymfocyty cytologie   imunologie   MeSH
• cytokiny metabolismus   MeSH
• DNA vazebné proteiny metabolismus   MeSH
• histokompatibilita - antigeny metabolismus   MeSH
• messenger RNA genetika   metabolismus   MeSH
• myši inbrední C57BL MeSH
• protein PEBP2A3 metabolismus   MeSH
• receptory antigenů T-buněk metabolismus   MeSH
• regulace genové exprese MeSH
• signální transdukce MeSH
• thymus cytologie   imunologie   MeSH
• transkripční faktory metabolismus   MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

Overtly self-reactive T cells are removed during thymic selection. However, it has been recently established that T cell self-reactivity promotes protective immune responses. Apparently, the level of self-reactivity of mature T cells must be tightly balanced. Our mathematical model and experimental data show that the dynamic regulation of CD4- and CD8-LCK coupling establish the self-reactivity of the peripheral T cell pool. The stoichiometry of the interaction between CD8 and LCK, but not between CD4 and LCK, substantially increases upon T cell maturation. As a result, peripheral CD8+ T cells are more self-reactive than CD4+ T cells. The different levels of self-reactivity of mature CD8+ and CD4+ T cells likely reflect the unique roles of these subsets in immunity. These results indicate that the evolutionary selection pressure tuned the CD4-LCK and CD8-LCK stoichiometries, as they represent the unique parts of the proximal T cell receptor (TCR) signaling pathway, which differ between CD4+ and CD8+ T cells.

• MeSH
• antigeny metabolismus   MeSH
• buněčná diferenciace MeSH
• CD4-pozitivní T-lymfocyty cytologie   metabolismus   MeSH
• CD8-pozitivní T-lymfocyty cytologie   metabolismus   MeSH
• homeostáza MeSH
• myši inbrední C57BL MeSH
• signální transdukce MeSH
• tyrosinkinasa p56(lck), specifická pro lymfocyty metabolismus   MeSH
• vazba proteinů MeSH
• zvířata MeSH
• Check Tag
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Little attention was given to the interaction between tumor and stromal cells in urothelial bladder carcinoma (UBC). While recent studies point towards the existence of different fibroblast subsets, no comprehensive analyses linking different fibroblast markers to UBC patient survival have been performed so far. Through immunohistochemical analysis of five selected fibroblast markers, namely alpha smooth muscle actin (ASMA), CD90/Thy-1, fibroblast activation protein (FAP), platelet derived growth factor receptor-alpha and -beta (PDGFRa,-b), this study investigates their association with survival and histopathological characteristics in a cohort of 344 UBC patients, involving both, muscle-invasive and non-muscle-invasive cases. The data indicates that combinations of stromal markers are more suited to identify prognostic patient subgroups than single marker analysis. Refined stroma-marker-based patient stratification was achieved through cluster analysis and identified a FAP-dominant patient cluster as independent marker for shorter 5-year-survival (HR(95% CI)2.25(1.08-4.67), p = 0.030). Analyses of interactions between fibroblast and CD8a-status identified a potential minority of cases with CD90-defined stroma and high CD8a infiltration showing a good prognosis of more than 80% 5-year-survival. Presented analyses point towards the existence of different stroma-cell subgroups with distinct tumor-modulatory properties and motivate further studies aiming to better understand the molecular tumor-stroma crosstalk in UBC.

• MeSH
• aktiny metabolismus   MeSH
• antigeny Thy-1 metabolismus   MeSH
• CD8-pozitivní T-lymfocyty cytologie   imunologie   metabolismus   MeSH
• fenotyp MeSH
• fibroblasty cytologie   metabolismus   MeSH
• Kaplanův-Meierův odhad MeSH
• lidé MeSH
• membránové proteiny metabolismus   MeSH
• nádorové biomarkery metabolismus   MeSH
• nádory močového měchýře metabolismus   mortalita   patologie   MeSH
• prognóza MeSH
• proporcionální rizikové modely MeSH
• růstový faktor odvozený z trombocytů - receptor alfa metabolismus   MeSH
• senioři MeSH
• serinové endopeptidasy metabolismus   MeSH
• shluková analýza MeSH
• želatinasy metabolismus   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Isoxazole is a five-membered heterocycle that is widely used in drug discovery endeavors. Here, we report the design, synthesis, and structural and biological characterization of SS-208, a novel HDAC6-selective inhibitor containing the isoxazole-3-hydroxamate moiety as a zinc-binding group as well as a hydrophobic linker. A crystal structure of the Danio rerio HDAC6/SS-208 complex reveals a bidentate coordination of the active-site zinc ion that differs from the preferred monodentate coordination observed for HDAC6 complexes with phenylhydroxamate-based inhibitors. While SS-208 has minimal effects on the viability of murine SM1 melanoma cells in vitro, it significantly reduced in vivo tumor growth in a murine SM1 syngeneic melanoma mouse model. These findings suggest that the antitumor activity of SS-208 is mainly mediated by immune-related antitumor activity as evidenced by the increased infiltration of CD8+ and NK+ T cells and the enhanced ratio of M1 and M2 macrophages in the tumor microenvironment.

• MeSH
• CD8-pozitivní T-lymfocyty cytologie   MeSH
• dánio pruhované MeSH
• histondeacetylasa 6 antagonisté a inhibitory   MeSH
• inhibitory histondeacetylas chemie   farmakologie   MeSH
• isoxazoly chemie   farmakologie   MeSH
• katalytická doména MeSH
• kyseliny hydroxamové chemie   farmakologie   MeSH
• lidé MeSH
• makrofágy cytologie   MeSH
• melanom farmakoterapie   MeSH
• mikrozomy chemie   MeSH
• myši MeSH
• nádorové buněčné linie MeSH
• NKT buňky cytologie   MeSH
• objevování léků MeSH
• transplantace izogenní MeSH
• zinek chemie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

The interaction of T-cell receptors (TCRs) with self- and non-self-peptides in the major histocompatibility complex (MHC) stimulates crucial signaling events, which in turn can activate T lymphocytes. A variety of accessory molecules further modulate T-cell signaling. Of these, the CD4 and CD8 coreceptors make the most critical contributions to T cell sensitivity in vivo. Whereas, CD4 function in T cell development is well-characterized, its role in peripheral T cells remains incompletely understood. It was originally suggested that CD4 stabilizes weak interactions between TCRs and peptides in the MHC and delivers Lck kinases to that complex. The results of numerous experiments support the latter role, indicating that the CD4-Lck complex accelerates TCR-triggered signaling and controls the availability of the kinase for TCR in the absence of the ligand. On the other hand, extremely low affinity of CD4 for MHC rules out its ability to stabilize the receptor-ligand complex. In this review, we summarize the current knowledge on CD4 in T cells, with a special emphasis on the spatio-temporal organization of early signaling events and the relevance for CD4 function. We further highlight the capacity of CD4 to interact with the MHC in the absence of TCR. It drives the adhesion of T cells to the cells that express the MHC. This process is facilitated by the CD4 accumulation in the tips of microvilli on the surface of unstimulated T cells. Based on these observations, we suggest an alternative model of CD4 role in T-cell activation.

• MeSH
• aktivace lymfocytů * MeSH
• CD4-pozitivní T-lymfocyty cytologie   imunologie   MeSH
• CD8-pozitivní T-lymfocyty cytologie   metabolismus   MeSH
• histokompatibilita - antigeny imunologie   MeSH
• lidé MeSH
• receptory antigenů T-buněk imunologie   MeSH
• signální transdukce imunologie   MeSH
• tyrosinkinasa p56(lck), specifická pro lymfocyty imunologie   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

While autoimmune T cells are present in most individuals, only a minority of the population suffers from an autoimmune disease. To better appreciate the limits of T cell tolerance, we carried out experiments to determine how many autoimmune T cells are required to initiate an experimental autoimmune disease. Variable numbers of autoimmune OT-I T cells were transferred into RIP-OVA mice, which were injected with antigen-loaded DCs in a single footpad; this restricted T cell priming to a few OT-I T cells that are present in the draining popliteal lymph node. Using selective plane illumination microscopy (SPIM) we counted the number of OT-I T cells present in the popliteal lymph node at the time of priming. Analysis of our data suggests that a single autoimmune T cell cannot induce an experimental autoimmune disease, but a "quorum" of 2-5 autoimmune T cells clearly has this capacity.

• MeSH
• autoimunita * MeSH
• autoimunitní nemoci imunologie   MeSH
• CD8-pozitivní T-lymfocyty cytologie   imunologie   MeSH
• dendritické buňky imunologie   MeSH
• experimentální diabetes mellitus imunologie   MeSH
• imunologická tolerance MeSH
• lymfatické uzliny cytologie   imunologie   MeSH
• modely nemocí na zvířatech MeSH
• myši transgenní MeSH
• myši MeSH
• ovalbumin imunologie   MeSH
• převzatá imunita MeSH
• prezentace antigenu MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Mucosal-associated invariant T (MAIT) cells contain two main subpopulations, CD8(+) and double-negative (DN) cells. The first reports suggested that subpopulations of MAIT cells have similar phenotype and function. Recent works, however, demonstrate that the subpopulations have different ontogenesis and are differentially affected by xenobiotic treatment. In this work, we re-examined the possible differences between subpopulations of MAIT cells. We demonstrate that the main subpopulations of MAIT cells (CD8 and DN) are relatively uniform in terms of both phenotype and function. Both populations are memory/activated, tissue-homing and pro-inflammatory. CD8(+) MAIT cells are better equipped for pro-inflammatory functions as they express higher levels of CD16 and NKG2D, produce more pro-inflammatory cytokines (TNF-α and IFN-γ) and have higher cytotoxic potential (contain more granzyme B and express higher levels of CD107A upon stimulation). Our study contributes to the understanding of the heterogeneity of MAIT cell population.

• MeSH
• biologické markery metabolismus   MeSH
• buněčný rodokmen imunologie   MeSH
• CD8-pozitivní T-lymfocyty cytologie   imunologie   MeSH
• dospělí MeSH
• exprese genu MeSH
• GPI-vázané proteiny genetika   imunologie   MeSH
• granzymy genetika   imunologie   MeSH
• imunofenotypizace MeSH
• imunologická paměť * MeSH
• interferon gama genetika   imunologie   MeSH
• lektinové receptory NK-buněk - podrodina K genetika   imunologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• MAIT buňky cytologie   imunologie   MeSH
• membránový protein 1 asociovaný s lyzozomy genetika   imunologie   MeSH
• receptory IgG genetika   imunologie   MeSH
• TNF-alfa genetika   imunologie   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

The notion that alternative peptide substrates can be processed and presented to the MHC class I pathway has opened for new aspects on how the immune system detects infected or damaged cells. Recent works show that antigenic peptides are derived from intron sequences in pre-mRNAs target for the nonsense-mediated degradation pathway. Introns are spliced out co-transcriptionally suggesting that such pioneer translation products (PTPs) are synthesized on the nascent RNAs in the nuclear compartment to ensure that the first peptides to emerge from an mRNA are destined for the class I pathway. This illustrates an independent translation event during mRNA maturation that give rise to specific peptide products with a specific function in the immune system. The characterization of the translation apparatus responsible for PTP synthesis will pave the way for understanding how PTP production is regulated in different tissues under different conditions and will help designing new vaccine strategies.

• MeSH
• buněčné jádro genetika   imunologie   MeSH
• CD8-pozitivní T-lymfocyty cytologie   imunologie   MeSH
• cytosol imunologie   metabolismus   MeSH
• dendritické buňky cytologie   imunologie   metabolismus   MeSH
• fagozomy genetika   imunologie   MeSH
• histokompatibilita - antigeny třídy I genetika   imunologie   MeSH
• introny MeSH
• lidé MeSH
• peptidy genetika   imunologie   MeSH
• prekurzory RNA genetika   imunologie   MeSH
• prezentace antigenu genetika   MeSH
• proteasomový endopeptidasový komplex genetika   imunologie   MeSH
• proteosyntéza imunologie   MeSH
• sestřih RNA imunologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

Adenylate cyclase toxin (CyaA) is a key virulence factor of the whooping cough agent Bordetella pertussis. The toxin targets CD11b-expressing phagocytes and delivers into their cytosol an adenylyl cyclase (AC) enzyme that subverts cellular signaling by increasing cAMP levels. In the present study, we analyzed the modulatory effects of CyaA on adhesive, migratory and antigen presenting properties of Toll-like receptor (TLR)-activated murine and human dendritic cells (DCs). cAMP signaling of CyaA enhanced TLR-induced dissolution of cell adhesive contacts and migration of DCs towards the lymph node-homing chemokines CCL19 and CCL21 in vitro. Moreover, we examined in detail the capacity of toxin-treated DCs to induce CD4(+) and CD8(+) T cell responses. Exposure to CyaA decreased the capacity of LPS-stimulated DCs to present soluble protein antigen to CD4+ T cells independently of modulation of co-stimulatory molecules and cytokine production, and enhanced their capacity to promote CD4(+)CD25(+)Foxp3(+) T regulatory cells in vitro. In addition, CyaA decreased the capacity of LPS-stimulated DCs to induce CD8(+) T cell proliferation and limited the induction of IFN-γ producing CD8(+) T cells while enhancing IL-10 and IL-17-production. These results indicate that through activation of cAMP signaling, the CyaA may be mobilizing DCs impaired in T cell stimulatory capacity and arrival of such DCs into draining lymph nodes may than contribute to delay and subversion of host immune responses during B. pertussis infection.

• MeSH
• adenylátcyklasový toxin farmakologie   MeSH
• aktivace lymfocytů účinky léků   MeSH
• Bordetella pertussis chemie   MeSH
• buněčná adheze účinky léků   MeSH
• buněčná smrt účinky léků   MeSH
• CD antigeny metabolismus   MeSH
• CD8-pozitivní T-lymfocyty cytologie   účinky léků   imunologie   MeSH
• dendritické buňky cytologie   účinky léků   imunologie   MeSH
• lidé MeSH
• myši inbrední C57BL MeSH
• pohyb buněk účinky léků   MeSH
• proliferace buněk účinky léků   MeSH
• regulační T-lymfocyty účinky léků   MeSH
• rozpustnost MeSH
• toll-like receptory metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH