T cells are pivotal in the adaptive immune defense, necessitating a delicate balance between robust response against infections and self-tolerance. Their activation involves intricate cross-talk among signaling pathways triggered by the T-cell antigen receptors (TCR) and co-stimulatory or inhibitory receptors. The molecular regulation of these complex signaling networks is still incompletely understood. Here, we identify the adaptor protein ABIN1 as a component of the signaling complexes of GITR and OX40 co-stimulation receptors. T cells lacking ABIN1 are hyper-responsive ex vivo, exhibit enhanced responses to cognate infections, and superior ability to induce experimental autoimmune diabetes in mice. ABIN1 negatively regulates p38 kinase activation and late NF-κB target genes. P38 is at least partially responsible for the upregulation of the key effector proteins IFNG and GZMB in ABIN1-deficient T cells after TCR stimulation. Our findings reveal the intricate role of ABIN1 in T-cell regulation.

• MeSH
• adaptorové proteiny signální transdukční * metabolismus   genetika   MeSH
• aktivace lymfocytů imunologie   genetika   MeSH
• cytotoxické T-lymfocyty * imunologie   metabolismus   MeSH
• diabetes mellitus 1. typu imunologie   genetika   metabolismus   MeSH
• glukokortikoidy indukovaný protein související s TNRF MeSH
• interferon gama metabolismus   MeSH
• lidé MeSH
• mitogenem aktivované proteinkinasy p38 metabolismus   MeSH
• myši inbrední C57BL MeSH
• myši knockoutované MeSH
• myši MeSH
• NF-kappa B metabolismus   MeSH
• receptory antigenů T-buněk metabolismus   MeSH
• receptory OX40 metabolismus   genetika   MeSH
• signální transdukce * MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

The kinase LCK and CD4/CD8 co-receptors are crucial components of the T cell antigen receptor (TCR) signaling machinery, leading to key T cell fate decisions. Despite decades of research, the roles of CD4-LCK and CD8-LCK interactions in TCR triggering in vivo remain unknown. In this study, we created animal models expressing endogenous levels of modified LCK to resolve whether and how co-receptor-bound LCK drives TCR signaling. We demonstrated that the role of LCK depends on the co-receptor to which it is bound. The CD8-bound LCK is largely dispensable for antiviral and antitumor activity of cytotoxic T cells in mice; however, it facilitates CD8+ T cell responses to suboptimal antigens in a kinase-dependent manner. By contrast, the CD4-bound LCK is required for efficient development and function of helper T cells via a kinase-independent stabilization of surface CD4. Overall, our findings reveal the role of co-receptor-bound LCK in T cell biology, show that CD4- and CD8-bound LCK drive T cell development and effector immune responses using qualitatively different mechanisms and identify the co-receptor-LCK interactions as promising targets for immunomodulation.

• MeSH
• antigeny CD4 MeSH
• antigeny CD8 metabolismus   MeSH
• cytotoxické T-lymfocyty * metabolismus   MeSH
• myši MeSH
• receptory antigenů T-buněk metabolismus   MeSH
• signální transdukce MeSH
• tyrosinkinasa p56(lck), specifická pro lymfocyty * metabolismus   MeSH
• zvířata MeSH
• Check Tag
• myši MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

Neutrofily sú centrálnou zložkou vrodeného imunitného systému. V posledných rokoch si získali značnú pozornosť vďaka novoobjaveným biologickým efektorovým funkciám a ich zapojeniu do rôznych patologických stavov. Neutrofily predstavujú prvú líniu obrany imunitného systému a pôsobia ako fyzická a chemická bariéra proti patogénom. Aktivované neutrofily môžu okrem iného uvoľňovať svoj obsah – dekondenzovaný chromatín spolu s antimikrobiálnymi granulárnymi proteínmi, a vytvárať tak tzv. neutrofilové extracelulárne pasce (neutrophil extracellular traps – NETs). Tvorba NETov sa spúšťa kontaktom s rôznymi prozápalovými stimulmi, vrátane mikroorganizmov, cytokínov, imunitných komplexov a iných. V súčasnosti sú popísané dva základné mechanizmy tvorby NETov. Klasický spôsob je jednou z foriem programovanej bunkovej smrti závislým od NADPH-oxidázy, pričom je najlepšie preskúmaným mechanizmom. Druhý spôsob tvorby NETov charakterizuje rapídna bunková odpoveď na vonkajší stimul, pričom pasca sa uvoľní bez porušenia bunkovej membrány, takže nedochádza k usmrteniu neutrofilu. Zatiaľ čo NETy sú veľmi účinné pri eliminácii patogénov, môžu tiež spôsobiť vážne poškodenie, ak sa uvoľnia v nadmernom množstve alebo ich odstraňovanie nie je efektívne. Cieľom tohto článku je sprostredkovať pohľad na úlohu neutrofilov a spôsob tvorby NETov v závislosti od rôznych stimulov. Tiež sumarizuje súčasné poznatky o úlohe NETov v patofyziológii infekcií močových ciest a hemolyticko-uremického syndrómu indukovaného infekciou E. coli.

Neutrophils are a central component of the innate immune system. In recent years, neutrophils have gained considerable attention due to their newly discovered biological effector functions and their involvement in various pathological conditions. Neutrophils represent the first line of the immune system defense and act as a physical and chemical barrier against pathogens. Activated neutrophils can release contents – decondensed chromatin along with antimicrobial granular proteins creating neutrophil extracellular traps (NETs). The NET formation is triggered by the contact with various pro-inflammatory stimuli, including microorganisms, cytokines, immune complexes, and others. Currently, we know two basic mechanisms of NET formation. The classical way is one of the forms of programmed cell death dependent on NADPH-oxidase; it is the best described mechanism. The second way of NET formation is characterized by a rapid cellular response to an external stimulus, whereby the trap is released without breaking the cell membrane, so that the neutrophil is not killed. While NETs are very effective at eliminating pathogens, they can also cause serious damage if released in excess or removed inefficiently. This review provides a simple and comprehensible view of the role of neutrophils and the mechanism of NET formation depending on various stimuli, and also summarizes the current knowledge on the role of NETs in the pathophysiology of urinary tract infections and hemolytic uremic syndrome induced by E. coli infection.

• MeSH
• infekce močového ústrojí * patofyziologie   MeSH
• ledviny patologie   MeSH
• lidé MeSH
• neutrofily * MeSH
• přirozená imunita MeSH
• zánět patofyziologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• práce podpořená grantem MeSH
• přehledy MeSH

Engagement of PRRs in recognition of PAMPs or DAMPs is one of the processes that initiates cellular stress. These sensors are involved in signaling pathways leading to induction of innate immune processes. Signaling initiated by PRRs is associated with the activation of MyD88-dependent signaling pathways and myddosome formation. MyD88 downstream signaling depends upon the context of signaling initiation, the cell (sub)type and the microenvironment of signal initiation. Recognition of PAMPs or DAMPs through PRRs activates the cellular autonomous defence mechanism, which orchestrates the cell responses to resolve specific insults at the single cell level. In general, stressed endoplasmic reticulum is directly linked with the induction of autophagy and initiation of mitochondrial stress. These processes are regulated by the release of Ca2+ from ER stores accepted by mitochondria, which respond through membrane depolarization and the production of reactive oxygen species generating signals leading to inflammasome activation. In parallel, signaling from PRRs initiates the accumulation of misfolded or inappropriately post-translationally modified proteins in the ER and triggers a group of conserved emergency rescue pathways known as unfolded protein response. The cell-autonomous effector mechanisms have evolutionarily ancient roots and were gradually specialized for the defence of specific cell (sub)types. All of these processes are common to the innate immune recognition of microbial pathogens and tumorigenesis as well. PRRs are active in both cases. Downstream are activated signaling pathways initiated by myddosomes, translated by the cellular autonomous defence mechanism, and finalized by inflammasomes.

• Publikační typ
• časopisecké články MeSH

Natural killer (NK) cells are a family of lymphocytes with a natural ability to kill infected, harmed, or malignantly transformed cells. As these cells are part of the innate immunity, the cytotoxic mechanisms are activated upon recognizing specific patterns without prior antigen sensitization. This recognition is crucial for NK cell function in the maintenance of homeostasis and immunosurveillance. NK cells not only act directly toward malignant cells but also participate in the complex immune response by producing cytokines or cross-talk with other immune cells. Cancer may be seen as a break of all immune defenses when malignant cells escape the immunity and invade surrounding tissues creating a microenvironment supporting tumor progression. This process may be reverted by intervening immune response with immunotherapy, which may restore immune recognition. NK cells are important effector cells for immunotherapy. They may be used for adoptive cell transfer, genetically modified with chimeric antigen receptors, or triggered with appropriate antibodies and other antibody-fragment-based recombinant therapeutic proteins tailored specifically for NK cell engagement. NK cell receptors, responsible for target recognition and activation of cytotoxic response, could also be targeted in immunotherapy, for example, by various bi-, tri-, or multi-specific fusion proteins designed to bridge the gap between tumor markers present on target cells and activation receptors expressed on NK cells. However, this kind of immunoactive therapeutics may be developed only with a deep functional and structural knowledge of NK cell receptor: ligand interactions. This review describes the recent developments in the fascinating protein-engineering field of NK cell immunotherapeutics.

• MeSH
• buňky NK patologie   MeSH
• chimerické antigenní receptory * terapeutické užití   MeSH
• imunologické faktory MeSH
• imunoterapie adoptivní MeSH
• imunoterapie MeSH
• lidé MeSH
• nádorové mikroprostředí MeSH
• nádory * MeSH
• protinádorové látky * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• přehledy MeSH

Uveální melanom (UM) je onemocnění, které se významně liší od kožního melanomu – vyznačuje se nízkou nádorovou mutační náloží a 1letým celkovým přežitím přibližně 50 % (v případě metastatického onemocnění). Jedná se o vzácný tumor, u kterého na rozdíl od kožního melanomu není účinná léčba inhibitory tyrosinkinázy nebo inhibitory imunitního kontrolního bodu. Glykoprotein 100 (gp100) je protein vysoce exprimovaný v melanocytech a melanomu, a proto je vhodným antigenem pro specifickou imunoterapii. Tebentafusp je bispecifický uměle vytvořený protein, který patří do skupiny imunomobilizujících monoklonálních protilátek, které aktivují T-buněčné receptory (ImmTAC – Immune mobilising monoclonal T-cell receptors Against Cancer), které zprostředkují aktivizaci efektorových buněk a spustí imunitní reakce proti nádorovým buňkám. Tebentafusp je první molekulou tohoto typu, která byla použita v léčbě solidního nádoru. Cílí na nádorové buňky, které exprimují peptid gp100 prezentovaný HLA-A*02:01, a vytvořená imunitní synapse je schopna cíleně zabíjet nádorové buňky. Nedávno byla publikována randomizovaná studie III. fáze, kde léčba s tebentafuspem poprvé významně prodloužila celkové přežití u pacientů s neléčeným metastatickým uveálním melanomem. Mechanismus účinku tebentafuspu je novou strategií léčby pro pacienty s uveálním melanomem, a nejen pro ně.

Uveal melanoma (UM) is a disease that differs significantly from cutaneous melanoma mainly in the low mutational burden of the tumor and the 1-year overall survival of approximately 50% in patients with metastatic uveal melanoma. It is a rare tumor for which, unlike cutaneous melanoma, treatment with tyrosine kinase inhibitors or immune checkpoint inhibitors is ineffective. Glycoprotein 100 (gp100) is a protein highly expressed in melanocytes and melanoma and therefore it is a suitable antigen for specific immunotherapy. Tebentafusp is a bispecific engineered protein that belongs to a group of immunomobilizing monoclonal antibodies that activate T cell receptors (ImmTAC – Immune mobilising monoclonal T-cell receptors Against Cancer), which mediate the activation of effector cells and trigger immune responses against tumor cells. Tebentafusp is the first molecule of its type to be used in the treatment of a solid tumor. It targets tumor cells that express the gp100 peptide presented by HLA-A*02:01 and the formed immune synapse is able to target tumor cells. Recently was published a randomized phase III trial, where treatment with tebentafusp significantly prolonged overall survival in patients with untreated metastatic uveal melanoma for the first time. The mechanism of action of tebentafusp is a new treatment strategy for uveal melanoma patients, and not only for them.

• Klíčová slova
• tebentafusp,
• MeSH
• analýza přežití MeSH
• doba přežití bez progrese choroby MeSH
• klinické zkoušky jako téma MeSH
• lidé MeSH
• nádory uvey * farmakoterapie   genetika   klasifikace   patologie   MeSH
• nežádoucí účinky léčiv epidemiologie   klasifikace   MeSH
• rekombinantní fúzní proteiny * aplikace a dávkování   farmakologie   škodlivé účinky   MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• přehledy MeSH

Calcium influx through plasma membrane calcium release-activated calcium (CRAC) channels, which are formed of hexamers of Orai1, is a potent trigger for many important biological processes, most notably in T cell-mediated immunity. Through a bioinformatics-led cell biological screen, we have identified Orai1 as a substrate for the rhomboid intramembrane protease RHBDL2. We show that RHBDL2 prevents stochastic calcium signaling in unstimulated cells through conformational surveillance and cleavage of inappropriately activated Orai1. A conserved disease-linked proline residue is responsible for RHBDL2's recognizing the active conformation of Orai1, which is required to sharpen switch-like signaling triggered by store-operated calcium entry. Loss of RHBDL2 control of CRAC channel activity causes severe dysregulation of downstream CRAC channel effectors, including transcription factor activation, inflammatory cytokine expression, and T cell activation. We propose that this surveillance function may represent an ancient activity of rhomboid proteases in degrading unwanted signaling proteins.

• MeSH
• aktivace lymfocytů MeSH
• buněčná membrána metabolismus   MeSH
• Drosophila melanogaster MeSH
• gating iontového kanálu MeSH
• HEK293 buňky MeSH
• konformace proteinů MeSH
• lidé MeSH
• membránové proteiny metabolismus   MeSH
• mutace MeSH
• proteasy chemie   MeSH
• protein ORAI1 chemie   MeSH
• serinové endopeptidasy metabolismus   MeSH
• signální transdukce MeSH
• stochastické procesy MeSH
• vápník metabolismus   MeSH
• vápníková signalizace fyziologie   MeSH
• vápníkové kanály chemie   MeSH
• vazba proteinů MeSH
• výpočetní biologie MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

Therapy targeting immune checkpoints represents an integral part of the treatment for patients suffering from advanced melanoma. However, the mechanisms of resistance are responsible for a lower therapeutic outcome than expected. Concerning melanoma, insufficient stimulation of the immune system by tumour neoantigens is a likely explanation. As shown previously, radiotherapy is a known option for increasing the production of tumour neoantigens and their release into the microenvironment. Consequently, neoantigens could be recognized by antigen presenting cells (APCs) and subjected to effector T lymphocytes. Enhancing the immune reaction can trigger the therapeutic response also at distant metastases, a phenomenon known as an abscopal effect (from "ab scopus", that is, away from the target). To illustrate this, we present the case of a 78-year old male treated by anti-CTLA-4/ipilimumab for metastatic melanoma. The patient received the standard four doses of ipilimumab administered every three weeks. However, the control CT scans detected disease progression in the form of axillary lymph nodes metastasis and liver metastasis two months after ipilimumab. At this stage, palliative cryotherapy of the skin metastases was initiated to alleviate the tumour burden. Surprisingly, the effect of cryotherapy was also observed in untreated metastases and deep subcutaneous metastases on the back. Moreover, we observed the disease remission of axillary lymph nodes and liver metastasis two months after the cryotherapy. The rarity of the abscopal effect suggests that even primed anti-tumour CD8+ T cells cannot overcome the tumour microenvironment's suppressive effect and execute immune clearance. However, the biological mechanism underlying this phenomenon is yet to be elucidated. The elicitation of a systemic response by cryotherapy with documented abscopal effect was rarely reported, although the immune response induction is presumably similar to a radiotherapy-induced one. The report is a combination case study and review of the abscopal effect in melanoma treated with checkpoint inhibitors.

• MeSH
• antigen prezentující buňky imunologie   MeSH
• antigeny nádorové metabolismus   MeSH
• inhibitory kontrolních bodů terapeutické užití   MeSH
• ipilimumab terapeutické užití   MeSH
• kryoterapie MeSH
• lidé MeSH
• melanom imunologie   sekundární   terapie   MeSH
• modely imunologické MeSH
• nádorové mikroprostředí imunologie   MeSH
• nádory kůže imunologie   patologie   terapie   MeSH
• paliativní péče MeSH
• senioři MeSH
• výsledek terapie MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• Publikační typ
• časopisecké články MeSH
• kazuistiky MeSH
• přehledy MeSH

PURPOSE OF REVIEW: RTX toxin action often defines the outcome of bacterial infections. Here, we discuss the progress in understanding the impacts of RTX toxin activities on host immunity. RECENT FINDINGS: Bordetella pertussis CyaA activity paralyzes sentinel phagocytic cells by elevating cellular cAMP levels and blocks differentiation of infiltrating monocytes into bactericidal macrophages, promoting also de-differentiation of resident alveolar macrophages into monocyte-like cells. Vibrio cholerae multifunctional autoprocessing repeats-in-toxins (MARTX), through Rho inactivating and α/β-hydrolase (ABH) domain action blocks mitogen-activated protein kinase signaling in epithelial cells and dampens the inflammatory responses of intestinal epithelia by blocking immune cell recruitment. The action of actin crosslinking effector domain and Ras/Rap1-specific endopeptidase (RRSP) domains of MARTX compromises the phagocytic ability of macrophages. Aggregatibacter actinomycetemcomitans LtxA action triggers neutrophil elastase release into periodontal tissue, compromising the epithelial barrier and promoting bacterial spreads into deeper tissue. SUMMARY: Action of RTX toxins enables bacterial pathogens to cope with the fierce host immune defenses. RTX toxins often block phagocytosis and bactericidal reactive oxygen species and NO production. Some RTX toxins can reprogram the macrophages to less bactericidal cell types. Autophagy is hijacked for example by the activity of the V. cholerae ABH effector domain of the MARTX protein. Subversion of immune functions by RTX toxins thus promotes bacterial survival and proliferation in the host.

• MeSH
• adaptivní imunita MeSH
• Bacteria metabolismus   patogenita   MeSH
• bakteriální toxiny toxicita   MeSH
• buňky NK účinky léků   MeSH
• dendritické buňky účinky léků   MeSH
• epitelové buňky účinky léků   MeSH
• lidé MeSH
• makrofágy účinky léků   MeSH
• monocyty účinky léků   MeSH
• virulence MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

An aberrant immune response developed early in life may trigger inflammatory bowel disease (IBD) and food allergies (e.g., celiac disease). Fecal levels of immune markers categorize an inflammatory response (e.g., food allergy, autoimmune) paralleled with the initial microbial colonization. The immunoaffinity assays are routinely applied to quantify circulating immune protein markers in blood/serum. However, a reliable, multiplex assay to quantify fecal levels of immune proteins is unavailable. We developed mass spectrometry assays to simultaneously quantify fecal calprotectin, myeloperoxidase, eosinophil-derived neurotoxin, eosinophil cationic protein, alpha-1-antitrypsin 1, and adaptive immunity effectors in 134 neonatal stool swabs. We optimized extraction and proteolytic protocol and validated the multiplex assay in terms of linearity of response (> 100; typically 0.04 to 14.77 µg/mg of total protein), coefficient of determination (R2; > 0.99), the limit of detection (LOD; 0.003 to 0.04 µg/mg of total protein), the limit of quantification (LOQ; 0.009 to 0.122 µg/mg of total protein) and robustness. The median CV of intra- and interday precision was 9.8% and 14.1%, respectively. We quantified breast milk-derived IGHA2 to differentiate meconium from feces samples and to detect the first food intake. An early life profiling of immune markers reflects disrupted intestinal homeostasis, and it is perhaps suitable for pre-symptomatic interception of IBD and food allergies.

• MeSH
• biologické markery metabolismus   MeSH
• chemické techniky analytické metody   MeSH
• feces chemie   MeSH
• hmotnostní spektrometrie metody   MeSH
• idiopatické střevní záněty etiologie   metabolismus   MeSH
• lidé MeSH
• novorozenec MeSH
• odběr biologického vzorku metody   MeSH
• potravinová alergie etiologie   metabolismus   MeSH
• zánět diagnóza   mikrobiologie   MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• novorozenec MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH