11 results on '"Konjar Š"'
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2. Intestinal tissue-resident T cell activation depends on metabolite availability.
- Author
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Konjar Š, Ferreira C, Carvalho FS, Figueiredo-Campos P, Fanczal J, Ribeiro S, Morais VA, and Veldhoen M
- Subjects
- Intestinal Mucosa cytology, Intestines cytology, Lymphocyte Activation, Oxidative Phosphorylation, CD8-Positive T-Lymphocytes cytology, Intraepithelial Lymphocytes cytology, Memory T Cells cytology
- Abstract
The metabolic capacity of many cells is tightly regulated and can adapt to changes in metabolic resources according to environmental changes. Tissue-resident memory (T
RM ) CD8+ T cells are one of the most abundant T cell populations and offer rapid protection against invading pathogens, especially at the epithelia. TRM cells metabolically adapt to their tissue niche, such as the intestinal epithelial barrier. In the small intestine, the types of TRM cells are intraepithelial lymphocytes (IELs), which contain high levels of cytotoxic molecules and express activation markers, suggesting a heightened state of activation. We hypothesize that the tissue environment may determine IEL activity. We show that IEL activation, in line with its semiactive status, is metabolically faster than circulating CD8+ T cells. IEL glycolysis and oxidative phosphorylation (OXPHOS) are interdependently regulated and are dependent on rapid access to metabolites from the environment. IELs are restrained by local availability of metabolites, but, especially, glucose levels determine their activity. Importantly, this enables functional control of intestinal TRM cells by metabolic means within the fragile environment of the intestinal epithelial barrier.- Published
- 2022
- Full Text
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3. Heterogeneity of tissue resident memory T cells.
- Author
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Konjar Š, Ficht X, Iannacone M, and Veldhoen M
- Subjects
- Animals, CD8-Positive T-Lymphocytes, Memory T Cells, Mice, Immunologic Memory, Neoplasms
- Abstract
Non-lymphoid organs, in mice and humans, contain CD8
+ tissue-resident memory T (TRM ) cells. They play important roles in tissue homoeostasis as well as defence against infections and cancer. TRM cells have common characteristics that enables their tissue residency and function. However, the wide variety of tissues, some with continually exposure to invading microbes, distinct organ structures and functions, impose tissue-specific differences on TRM cells. Upon tissue-entry, they need to adapt to local circumstances by modifying their transcriptional machinery, enabling interactions with the - often specialised - surrounding cells and available metabolites. Heterogeneity amongst TRM cells may have implications for their defence function, organ-specific autoimmunity and chronic immune disorders. Here we indicate shared and unique TRM cell features within different tissues to provide a better understanding of their function and discuss possible future research directions., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)- Published
- 2022
- Full Text
- View/download PDF
4. The fungal Clitocybe nebularis lectin binds distinct cell surface glycoprotein receptors to induce cell death selectively in Jurkat cells.
- Author
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Perišić Nanut M, Žurga S, Konjar Š, Prunk M, Kos J, and Sabotič J
- Subjects
- Humans, Jurkat Cells, Agaricales physiology, Cell Death, Lectins metabolism, Membrane Glycoproteins metabolism, Plant Lectins metabolism, Receptors, N-Acetylglucosamine metabolism
- Abstract
Clitocybe nebularis lectin (CNL) is a GalNAcβ1-4GlcNAc-binding lectin that exhibits an antiproliferative effect exclusively on the Jurkat leukemic T cell line by provoking homotypic aggregation and dose-dependent cell death. Cell death of Jurkat cells exhibited typical features of early apoptosis, but lacked the activation of initiating and executing caspases. None of the features of CNL-induced cell death were effectively blocked with the pan-caspase inhibitor or different cysteine peptidase inhibitors. Furthermore, CNL binding induced Jurkat cells to release the endogenous damage-associated molecular pattern molecule high-mobility group box 1 (HMGB1). A plant lectin with similar glycan-binding specificity, Wisteria floribunda agglutinin (WFA) showed less selective toxicity and induced cell death in Jurkat, Tall-104, and Hut-87 cell lines. HMGB1 release was also detected when Jurkat cells were treated with WFA. We identified the CD45 and CD43 cell surface glycoproteins on Jurkat cells as the main targets for CNL binding. However, the blockade of CD45 phosphatase activity failed to block either CNL-induced homotypic agglutination or cell death. Overall, our results indicate that CNL triggers atypical cell death selectively on Jurkat cells, suggesting the potential applicability of CNL in novel strategies for treating and/or detecting acute T cell leukemia., (© 2022 The Authors. The FASEB Journal published by Wiley Periodicals LLC on behalf of Federation of American Societies for Experimental Biology.)
- Published
- 2022
- Full Text
- View/download PDF
5. Regulation of Oxygen Homeostasis at the Intestinal Epithelial Barrier Site.
- Author
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Konjar Š, Pavšič M, and Veldhoen M
- Subjects
- Animals, Cell Hypoxia, Homeostasis, Humans, Inflammatory Bowel Diseases metabolism, Inflammatory Bowel Diseases microbiology, Intestinal Mucosa microbiology, Gastrointestinal Microbiome, Intestinal Mucosa metabolism, Oxygen metabolism
- Abstract
The unique biology of the intestinal epithelial barrier is linked to a low baseline oxygen pressure (pO
2 ), characterised by a high rate of metabolites circulating through the intestinal blood and the presence of a steep oxygen gradient across the epithelial surface. These characteristics require tight regulation of oxygen homeostasis, achieved in part by hypoxia-inducible factor (HIF)-dependent signalling. Furthermore, intestinal epithelial cells (IEC) possess metabolic identities that are reflected in changes in mitochondrial function. In recent years, it has become widely accepted that oxygen metabolism is key to homeostasis at the mucosae. In addition, the gut has a vast and diverse microbial population, the microbiota. Microbiome-gut communication represents a dynamic exchange of mediators produced by bacterial and intestinal metabolism. The microbiome contributes to the maintenance of the hypoxic environment, which is critical for nutrient absorption, intestinal barrier function, and innate and/or adaptive immune responses in the gastrointestinal tract. In this review, we focus on oxygen homeostasis at the epithelial barrier site, how it is regulated by hypoxia and the microbiome, and how oxygen homeostasis at the epithelium is regulated in health and disease.- Published
- 2021
- Full Text
- View/download PDF
6. Type 1 T reg cells promote the generation of CD8 + tissue-resident memory T cells.
- Author
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Ferreira C, Barros L, Baptista M, Blankenhaus B, Barros A, Figueiredo-Campos P, Konjar Š, Lainé A, Kamenjarin N, Stojanovic A, Cerwenka A, Probst HC, Marie JC, and Veldhoen M
- Subjects
- Adoptive Transfer, Animals, CD8-Positive T-Lymphocytes transplantation, Coccidiosis immunology, Coccidiosis parasitology, Disease Models, Animal, Eimeria immunology, Female, Humans, Integrin beta Chains metabolism, Male, Mice, Mice, Transgenic, Receptors, CXCR3 metabolism, T-Box Domain Proteins genetics, T-Box Domain Proteins metabolism, T-Lymphocytes, Regulatory metabolism, T-Lymphocytes, Regulatory transplantation, Transforming Growth Factor beta metabolism, CD8-Positive T-Lymphocytes immunology, Cell Communication immunology, Cell Differentiation immunology, Immunologic Memory, T-Lymphocytes, Regulatory immunology
- Abstract
Tissue-resident memory T (T
RM ) cells, functionally distinct from circulating memory T cells, have a critical role in protective immunity in tissues, are more efficacious when elicited after vaccination and yield more effective antitumor immunity, yet the signals that direct development of TRM cells are incompletely understood. Here we show that type 1 regulatory T (Treg ) cells, which express the transcription factor T-bet, promote the generation of CD8+ TRM cells. The absence of T-bet-expressing type 1 Treg cells reduces the presence of TRM cells in multiple tissues and increases pathogen burden upon infectious challenge. Using infection models, we show that type 1 Treg cells are specifically recruited to local inflammatory sites via the chemokine receptor CXCR3. Close proximity with effector CD8+ T cells and Treg cell expression of integrin-β8 endows the bioavailability of transforming growth factor-β in the microenvironment, thereby promoting the generation of CD8+ TRM cells.- Published
- 2020
- Full Text
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7. Dynamic Metabolic State of Tissue Resident CD8 T Cells.
- Author
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Konjar Š and Veldhoen M
- Subjects
- Animals, Cell Differentiation immunology, Epithelial Cells immunology, Humans, Lymphocyte Activation immunology, CD8-Positive T-Lymphocytes immunology
- Abstract
In the past years, there have been significant advances in the understanding of how environmental conditions alone or in conjunction with pathogen invasion affect the metabolism of T cells, thereby influencing their activation, differentiation, and longevity. Detailed insights of the interlinked processes of activation and metabolism can contribute to major advances in immunotherapies. Naive and memory T cells circulate the body. In a quiescent state with low metabolic demands, they predominantly use oxidative phosphorylation for their energy needs. Recognition of cognate antigen combined with costimulatory signals results in a proliferative burst and effector molecule production, requiring rapid release of energy, achieved via dynamically reprogramming metabolic pathways. After activation, most T cells succumb to activation induced cell death, but few differentiate into memory T cells. Of note, some memory T cells permanently occupy tissues without circulating. These, tissue resident T cells are predominantly CD8 T cells, maintained in a metabolic state distinct from naïve and circulating memory CD8 T cells with elements similar to effector CD8 T cells but without undergoing proliferative burst or secreting immune mediators. They continually interact with tissue cells as part of an immune surveillance network, are well-adapted to the tissues they have made their home and where they may encounter different metabolic environments. In this review, we will discuss recent insights in metabolic characteristics of CD8 T cell biology, with emphasis on tissue resident CD8 T cells at the epithelial barriers.
- Published
- 2019
- Full Text
- View/download PDF
8. Metabolic wiring of murine T cell and intraepithelial lymphocyte maintenance and activation.
- Author
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Veldhoen M, Blankenhaus B, Konjar Š, and Ferreira C
- Subjects
- Adaptive Immunity immunology, Animals, Cell Differentiation immunology, Cell Movement immunology, Immunologic Memory immunology, Mice, Energy Metabolism immunology, Intraepithelial Lymphocytes immunology, Intraepithelial Lymphocytes metabolism, Lymphocyte Activation immunology
- Abstract
Adaptive immunity critically depends on cell migration combined with clonal selection and rapid expansion of rare lymphocytes recognising their cognate antigen in secondary lymphoid organs. It has since become apparent that large populations of T cells are maintained in tissues, which do not migrate throughout the body and do not require clonal expansion. Murine intraepithelial lymphocytes (IELs), located in the skin and small intestines, are maintained in a state of semi-activation, in marked contrast to the quiescent condition naive and memory lymphocytes are kept in. The poised activation state of IELs, their location in the top layers of barrier organs and close bidirectional interactions with epithelial cells suggests IELs are part of a sophisticated strategy of immune-surveillance and compartmentalisation of immune responses. Recent murine studies have reemphasised the influence of metabolism in T-cell activation and differentiation, with different metabolic make up of naive, effector and memory T cells. Here we highlight and discuss some of the current insights on immunometabolism of IELs, with emphasis on novel data contrasting how IELs may be maintained in a semi-activated state and may become fully functional compared with conventional T cells., (© 2018 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)
- Published
- 2018
- Full Text
- View/download PDF
9. Mitochondria maintain controlled activation state of epithelial-resident T lymphocytes.
- Author
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Konjar Š, Frising UC, Ferreira C, Hinterleitner R, Mayassi T, Zhang Q, Blankenhaus B, Haberman N, Loo Y, Guedes J, Baptista M, Innocentin S, Stange J, Strathdee D, Jabri B, and Veldhoen M
- Subjects
- Animals, Cardiolipins metabolism, Cells, Cultured, Coccidiosis parasitology, Disease Models, Animal, Eimeria immunology, Female, Humans, Intestinal Mucosa immunology, Intraepithelial Lymphocytes cytology, Lymphocyte Activation, Male, Mice, Mice, Inbred C57BL, Mice, Transgenic, Microscopy, Electron, Transmission, Mitochondria immunology, Mitochondria ultrastructure, Mitochondrial Membranes immunology, Mitochondrial Membranes metabolism, Mitochondrial Membranes ultrastructure, Primary Cell Culture, T-Lymphocytes cytology, Coccidiosis immunology, Intestinal Mucosa cytology, Intraepithelial Lymphocytes immunology, Mitochondria metabolism, T-Lymphocytes immunology
- Abstract
Epithelial-resident T lymphocytes, such as intraepithelial lymphocytes (IELs) located at the intestinal barrier, can offer swift protection against invading pathogens. Lymphocyte activation is strictly regulated because of its potential harmful nature and metabolic cost, and most lymphocytes are maintained in a quiescent state. However, IELs are kept in a heightened state of activation resembling effector T cells but without cytokine production or clonal proliferation. We show that this controlled activation state correlates with alterations in the IEL mitochondrial membrane, especially the cardiolipin composition. Upon inflammation, the cardiolipin composition is altered to support IEL proliferation and effector function. Furthermore, we show that cardiolipin makeup can particularly restrict swift IEL proliferation and effector functions, reducing microbial containment capability. These findings uncover an alternative mechanism to control cellular activity, special to epithelial-resident T cells, and a novel role for mitochondria, maintaining cells in a metabolically poised state while enabling rapid progression to full functionality., (Copyright © 2018 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)
- Published
- 2018
- Full Text
- View/download PDF
10. Intestinal Barrier Interactions with Specialized CD8 T Cells.
- Author
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Konjar Š, Ferreira C, Blankenhaus B, and Veldhoen M
- Abstract
The trillions of microorganisms that reside in the gastrointestinal tract, essential for nutrient absorption, are kept under control by a single cell barrier and large amounts of immune cells. Intestinal epithelial cells (IECs) are critical in establishing an environment supporting microbial colonization and immunological tolerance. A large population of CD8
+ T cells is in direct and constant contact with the IECs and the intraepithelial lymphocytes (IELs). Due to their location, at the interphase of the intestinal lumen and external environment and the host tissues, they seem ideally positioned to balance immune tolerance and protection to preserve the fragile intestinal barrier from invasion as well as immunopathology. IELs are a heterogeneous population, with a large innate-like contribution of unknown specificity, intercalated with antigen-specific tissue-resident memory T cells. In this review, we provide a comprehensive overview of IEL physiology and how they interact with the IECs and contribute to immune surveillance to preserve intestinal homeostasis and host-microbial relationships.- Published
- 2017
- Full Text
- View/download PDF
11. Stefin B interacts with histones and cathepsin L in the nucleus.
- Author
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Čeru S, Konjar Š, Maher K, Repnik U, Križaj I, Benčina M, Renko M, Nepveu A, Žerovnik E, Turk B, and Kopitar-Jerala N
- Subjects
- Animals, Cell Cycle, Cell Line, Tumor, Cytosol metabolism, Fibroblasts metabolism, Fluorescence Resonance Energy Transfer methods, Histones metabolism, Humans, Mice, Models, Biological, Cathepsin L metabolism, Cell Nucleus metabolism, Cystatin B metabolism, Gene Expression Regulation, Histones chemistry
- Abstract
Stefin B (cystatin B) is an endogenous inhibitor of cysteine proteinases localized in the nucleus and the cytosol. Loss-of-function mutations in the stefin B gene (CSTB) gene were reported in patients with Unverricht-Lundborg disease (EPM1). We have identified an interaction between stefin B and nucleosomes, specifically with histones H2A.Z, H2B, and H3. In synchronized T98G cells, stefin B co-immunoprecipitated with histone H3, predominantly in the G(1) phase of the cell cycle. Stefin B-deficient mouse embryonic fibroblasts entered S phase earlier than wild type mouse embryonic fibroblasts. In contrast, increased expression of stefin B in the nucleus delayed cell cycle progression in T98G cells. The delay in cell cycle progression was associated with the inhibition of cathepsin L in the nucleus, as judged from the decreased cleavage of the CUX1 transcription factor. In vitro, inhibition of cathepsin L by stefin B was potentiated in the presence of histones, whereas histones alone did not affect the cathepsin L activity. Interaction of stefin B with the Met-75 truncated form of cathepsin L in the nucleus was confirmed by fluorescence resonance energy transfer experiments in the living cells. Stefin B could thus play an important role in regulating the proteolytic activity of cathepsin L in the nucleus, protecting substrates such as transcription factors from its proteolytic processing.
- Published
- 2010
- Full Text
- View/download PDF
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