492 results on '"Geisler, Carsten"'
Search Results
452. Antibiotics inhibit tumor and disease activity in cutaneous T-cell lymphoma.
- Author
-
Lindahl LM, Willerslev-Olsen A, Gjerdrum LMR, Nielsen PR, Blümel E, Rittig AH, Celis P, Herpers B, Becker JC, Stausbøl-Grøn B, Wasik MA, Gluud M, Fredholm S, Buus TB, Johansen C, Nastasi C, Peiffer L, Kubat L, Bzorek M, Eriksen JO, Krejsgaard T, Bonefeld CM, Geisler C, Mustelin T, Langhoff E, Givskov M, Woetmann A, Kilian M, Litman T, Iversen L, and Odum N
- Subjects
- Aged, Cell Proliferation drug effects, Female, Humans, Lymphoma, T-Cell, Cutaneous metabolism, Lymphoma, T-Cell, Cutaneous pathology, Male, Middle Aged, Prospective Studies, STAT3 Transcription Factor metabolism, Signal Transduction drug effects, Skin Neoplasms metabolism, Skin Neoplasms pathology, T-Lymphocytes drug effects, T-Lymphocytes metabolism, T-Lymphocytes pathology, Anti-Bacterial Agents therapeutic use, Lymphoma, T-Cell, Cutaneous drug therapy, Skin Neoplasms drug therapy
- Abstract
It has been proposed that CD4 T-cell responses to Staphylococcus aureus (SA) can inadvertently enhance neoplastic progression in models of skin cancer and cutaneous T-cell lymphoma (CTCL). In this prospective study, we explored the effect of transient antibiotic treatment on tumor cells and disease activity in 8 patients with advanced-stage CTCL. All patients experienced significant decrease in clinical symptoms in response to aggressive, transient antibiotic treatment. In some patients, clinical improvements lasted for more than 8 months. In 6 of 8 patients, a malignant T-cell clone could be identified in lesional skin, and a significant decrease in the fraction of malignant T cells was observed following antibiotics but an otherwise unchanged treatment regimen. Immunohistochemistry, global messenger RNA expression, and cell-signaling pathway analysis indicated that transient aggressive antibiotic therapy was associated with decreased expression of interleukin-2 high-affinity receptors (CD25), STAT3 signaling, and cell proliferation in lesional skin. In conclusion, this study provides novel evidence suggesting that aggressive antibiotic treatment inhibits malignant T cells in lesional skin. Thus, we provide a novel rationale for treatment of SA in advanced CTCL.
- Published
- 2019
- Full Text
- View/download PDF
453. Staphylococcal alpha-toxin tilts the balance between malignant and non-malignant CD4 + T cells in cutaneous T-cell lymphoma.
- Author
-
Blümel E, Willerslev-Olsen A, Gluud M, Lindahl LM, Fredholm S, Nastasi C, Krejsgaard T, Surewaard BGJ, Koralov SB, Hu T, Persson JL, Bonefeld CM, Geisler C, Iversen L, Becker JC, Andersen MH, Woetmann A, Buus TB, and Ødum N
- Abstract
Staphylococcus aureus is implicated in disease progression in cutaneous T-cell lymphoma (CTCL). Here, we demonstrate that malignant T cell lines derived from CTCL patients as well as primary malignant CD4
+ T cells from Sézary syndrome patients are considerably more resistant to alpha-toxin-induced cell death than their non-malignant counterparts. Thus, in a subset of Sézary syndrome patients the ratio between malignant and non-malignant CD4+ T cells increases significantly following exposure to alpha-toxin. Whereas toxin-induced cell death is ADAM10 dependent in healthy CD4+ T cells, resistance to alpha-toxin in malignant T cells involves both downregulation of ADAM10 as well as other resistance mechanisms. In conclusion, we provide first evidence that Staphylococcus aureus derived alpha-toxin can tilt the balance between malignant and non-malignant CD4+ T cells in CTCL patients. Consequently, alpha-toxin may promote disease progression through positive selection of malignant CD4+ T cells, identifying alpha-toxin as a putative drug target in CTCL., (© 2019 The Author(s). Published with license by Taylor & Francis Group, LLC.)- Published
- 2019
- Full Text
- View/download PDF
454. Single-cell heterogeneity in Sézary syndrome.
- Author
-
Buus TB, Willerslev-Olsen A, Fredholm S, Blümel E, Nastasi C, Gluud M, Hu T, Lindahl LM, Iversen L, Fogh H, Gniadecki R, Litvinov IV, Persson JL, Bonefeld CM, Geisler C, Christensen JP, Krejsgaard T, Litman T, Woetmann A, and Ødum N
- Subjects
- Aged, Aged, 80 and over, Female, Humans, Male, Middle Aged, Depsipeptides pharmacology, Drug Resistance, Neoplasm, Flow Cytometry, Histone Deacetylase Inhibitors pharmacology, Sezary Syndrome drug therapy, Sezary Syndrome metabolism, Sezary Syndrome pathology, T-Lymphocytes metabolism, T-Lymphocytes pathology, Vorinostat pharmacology
- Abstract
Sézary syndrome (SS) is an aggressive leukemic variant of cutaneous T-cell lymphoma (CTCL) with a median life expectancy of less than 4 years. Although initial treatment responses are often good, the vast majority of patients with SS fail to respond to ongoing therapy. We hypothesize that malignant T cells are highly heterogeneous and harbor subpopulations of SS cells that are both sensitive and resistant to treatment. Here, we investigate the presence of single-cell heterogeneity and resistance to histone deacetylase inhibitors (HDACi) within primary malignant T cells from patients with SS. Using single-cell RNA sequencing and flow cytometry, we find that malignant T cells from all investigated patients with SS display a high degree of single-cell heterogeneity at both the mRNA and protein levels. We show that this heterogeneity divides the malignant cells into distinct subpopulations that can be isolated by their expression of different surface antigens. Finally, we show that treatment with HDACi (suberanilohydroxamic acid and romidepsin) selectively eliminates some subpopulations while leaving other subpopulations largely unaffected. In conclusion, we show that patients with SS display a high degree of single-cell heterogeneity within the malignant T-cell population, and that distinct subpopulations of malignant T cells carry HDACi resistance. Our data point to the importance of understanding the heterogeneous nature of malignant SS cells in each individual patient to design combinational and new therapies to counter drug resistance and treatment failure., (© 2018 by The American Society of Hematology.)
- Published
- 2018
- Full Text
- View/download PDF
455. SATB1 in Malignant T Cells.
- Author
-
Fredholm S, Willerslev-Olsen A, Met Ö, Kubat L, Gluud M, Mathiasen SL, Friese C, Blümel E, Petersen DL, Hu T, Nastasi C, Lindahl LM, Buus TB, Krejsgaard T, Wasik MA, Kopp KL, Koralov SB, Persson JL, Bonefeld CM, Geisler C, Woetmann A, Iversen L, Becker JC, and Ødum N
- Subjects
- Cell Line, Tumor, Cohort Studies, Disease Progression, Gene Expression Regulation, Neoplastic genetics, Gene Expression Regulation, Neoplastic immunology, Gene Knockdown Techniques, Humans, Interleukin-5 immunology, Interleukin-5 metabolism, Interleukin-9 immunology, Interleukin-9 metabolism, Janus Kinase 3 metabolism, Matrix Attachment Region Binding Proteins metabolism, MicroRNAs genetics, MicroRNAs immunology, Mycosis Fungoides immunology, Mycosis Fungoides pathology, Neoplasm Staging, RNA, Small Interfering metabolism, STAT5 Transcription Factor genetics, STAT5 Transcription Factor metabolism, Signal Transduction genetics, Signal Transduction immunology, Skin Neoplasms immunology, Skin Neoplasms pathology, T-Lymphocytes metabolism, Matrix Attachment Region Binding Proteins genetics, MicroRNAs metabolism, Mycosis Fungoides genetics, Skin Neoplasms genetics, T-Lymphocytes immunology
- Abstract
Deficient expression of SATB1 hampers thymocyte development and results in inept T-cell lineages. Recent data implicate dysregulated SATB1 expression in the pathogenesis of mycosis fungoides, the most frequent variant of cutaneous T-cell lymphoma. Here, we report on a disease stage-associated decrease of SATB1 expression and an inverse expression of STAT5 and SATB1 in situ. STAT5 inhibited SATB1 expression through induction of microRNA-155. Decreased SATB1 expression triggered enhanced expression of IL-5 and IL-9 (but not IL-6 and IL-32), whereas increased SATB1 expression had the opposite effect, indicating that the microRNA-155 target SATB1 is a repressor of IL-5 and IL-9 in malignant T cells. In accordance, inhibition of STAT5 and its upstream activator JAK3 triggered increased SATB1 expression and a concomitant suppression of IL-5 and IL-9 expression in malignant T cells. In conclusion, we provide a mechanistic link between the proto-oncogenic JAK3/STAT5/microRNA-155 pathway, SATB1, and cytokines linked to CTCL severity and progression, indicating that SATB1 dysregulation is involved in cutaneous T-cell lymphoma pathogenesis., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2018
- Full Text
- View/download PDF
456. Increased Production of IL-17A-Producing γδ T Cells in the Thymus of Filaggrin-Deficient Mice.
- Author
-
Jee MH, Johansen JD, Buus TB, Petersen TH, Gadsbøll AØ, Woetmann A, Ødum N, Thyssen JP, White AJ, Anderson G, Geisler C, and Bonefeld CM
- Subjects
- Animals, Cell Differentiation, Filaggrin Proteins, Interleukin-23 genetics, Interleukin-6 genetics, Mice, Mice, Inbred C57BL, Mutation, Skin immunology, Spleen immunology, Thymus Gland immunology, Interleukin-17 immunology, Intermediate Filament Proteins deficiency, Intermediate Filament Proteins genetics, Receptors, Antigen, T-Cell, gamma-delta immunology, Th17 Cells immunology, Thymus Gland cytology
- Abstract
Mutations in the filaggrin gene ( Flg ) are associated with increased systemic levels of Th17 cells and increased IL-17A production following antigen exposure in both humans and mice. In addition to Th17 cells, γδ T cells can produce IL-17A. The differentiation of γδ T cells to either IFNγ or IL-17A-producing (γδT17) cells is mainly determined in the thymus. Interestingly, it has been reported that filaggrin is expressed in the Hassall bodies in the human thymic medulla. However, whether filaggrin affects γδ T cell development is not known. Here, we show that filaggrin-deficient flaky tail ( ft/ft ) mice have an increased number of γδT17 cells in the spleen, epidermis, and thymus compared to wild-type ( WT ) mice. We demonstrate that filaggrin is expressed in the mouse thymic medulla and that blocking the egress of cells from the thymus results in accumulation of Vγ2
+ γδT17 cells in the thymus of adult ft/ft mice. Finally, we find increased T cell receptor expression levels on γδ T cells and increased levels of IL-6 and IL-23 in the thymus of ft/ft mice. These findings demonstrate that filaggrin is expressed in the mouse thymic medulla and that production of Vγ2+ γδT17 cells is dysregulated in filaggrin-deficient ft/ft mice.- Published
- 2018
- Full Text
- View/download PDF
457. Interleukin-26 (IL-26) is a novel anti-microbial peptide produced by T cells in response to staphylococcal enterotoxin.
- Author
-
Woetmann A, Alhede M, Dabelsteen S, Bjarnsholt T, Rybtke M, Nastasi C, Krejsgaard T, Andersen MH, Bonefeld CM, Geisler C, Givskov M, and Odum N
- Abstract
Anti-microbial peptides are produced at outer and inner surfaces by epithelia and innate immune cells in response to bacterial infection. Staphylococcus aureus is an enterotoxin producing, Gram-positive pathogen, which is a major cause of soft tissue infections and life-threatening bacteremia and sepsis. Here we show that (i) skin T cells in chronic wounds infected with S. aureus express interleukin-26 (IL-26) in situ , (ii) staphylococcal enterotoxins (SE) trigger IL-26 expression in T cell lines and primary skin T cells, and (iii) IL-26 triggers death and inhibits biofilm formation and growth of S. aureus . Thus, we provide novel evidence that IL-26 is an anti-microbial peptide produced by T cells in response to SE. Accordingly, we propose that IL-26 producing T cells take part in the innate immune response to SE producing S. aureus and thus play a novel role in the primary innate immune defense in addition to their classical role in adaptive immunity., Competing Interests: CONFLICTS OF INTEREST The authors declare no competing financial interest.
- Published
- 2018
- Full Text
- View/download PDF
458. Three distinct developmental pathways for adaptive and two IFN-γ-producing γδ T subsets in adult thymus.
- Author
-
Buus TB, Ødum N, Geisler C, and Lauritsen JPH
- Subjects
- Animals, Antigens, CD immunology, Cell Differentiation, Interferon-gamma immunology, Interleukin-4 immunology, Mice, Natural Killer T-Cells cytology, Natural Killer T-Cells immunology, Proto-Oncogene Proteins c-kit immunology, Signal Transduction, T-Lymphocyte Subsets cytology, T-Lymphocytes cytology, Thymocytes cytology, Thymus Gland cytology, Lymphopoiesis immunology, Receptors, Antigen, T-Cell, gamma-delta immunology, T-Lymphocyte Subsets immunology, T-Lymphocytes immunology, Thymocytes immunology
- Abstract
Murine γδ T cells include subsets that are programmed for distinct effector functions during their development in the thymus. Under pathological conditions, different γδ T cell subsets can be protective or can exacerbate a disease. Here we show that CD117, CD200 and CD371, together with other markers, identify seven developmental stages of γδ T cells. These seven stages can be divided into three distinct developmental pathways that are enriched for different TCRδ repertoires and exhibit characteristic expression patterns associated with adaptive (γδTn), IFN-γ-producing (γδT1) and IFN-γ/IL-4-co-producing γδ T cells (γδNKT). Developmental progression towards both IFN-γ-producing subsets can be induced by TCR signalling, and each pathway results in thymic emigration at a different stage. Finally, we show that γδT1 cells are the predominating IFN-γ-producing subset developing in the adult thymus. Thus, this study maps out three distinct development pathways that result in the programming of γδTn, γδT1 and γδNKT cells.
- Published
- 2017
- Full Text
- View/download PDF
459. Butyrate and propionate inhibit antigen-specific CD8 + T cell activation by suppressing IL-12 production by antigen-presenting cells.
- Author
-
Nastasi C, Fredholm S, Willerslev-Olsen A, Hansen M, Bonefeld CM, Geisler C, Andersen MH, Ødum N, and Woetmann A
- Subjects
- CD8-Positive T-Lymphocytes immunology, Cells, Cultured, Coculture Techniques, Dendritic Cells immunology, Humans, Interleukin-23 metabolism, MART-1 Antigen metabolism, Butyrates pharmacology, CD8-Positive T-Lymphocytes drug effects, Dendritic Cells drug effects, Immunologic Factors pharmacology, Interleukin-12 metabolism, Propionates pharmacology
- Abstract
Short chain fatty acids (SCFAs), such as acetate, butyrate and propionate, are products of microbial macronutrients fermentation that distribute systemically and are believed to modulate host immune responses. Recent data have indicated that certain SCFAs, such as butyrate and propionate, directly modulate human dendritic cell (DC) function. Given the role of DCs in initiating and shaping the adaptive immune response, we now explore how SCFAs affect the activation of antigen-specific CD8
+ T cells stimulated with autologous, MART1 peptide-pulsed DC. We show that butyrate reduces the frequency of peptide-specific CD8+ T cells and, together with propionate, inhibit the activity of those cells. On the contrary, acetate does not affect them. Importantly, butyrate and propionate inhibit the production of IL-12 and IL-23 in the DCs and exogenous IL-12 fully restores the activation of the MART-1-specific CD8+ T cells, whereas IL-23 has no effect. In conclusion, these results point to a pivotal role of butyrate and propionate in modulating CD8+ T cell activation via the inhibition of IL-12 secretion from DCs. These findings reveal a novel mechanism whereby bacterial fermentation products may modulate CD8+ T cell function with possible implications in anti-cancer immunotherapy.- Published
- 2017
- Full Text
- View/download PDF
460. Substoichiometric ribose methylations in spliceosomal snRNAs.
- Author
-
Krogh N, Kongsbak-Wismann M, Geisler C, and Nielsen H
- Subjects
- Humans, Jurkat Cells, Methylation, RNA, Small Nuclear metabolism, Ribose chemistry, Ribose metabolism, Spliceosomes metabolism, Stereoisomerism, T-Lymphocytes chemistry, T-Lymphocytes metabolism, RNA, Small Nuclear chemistry, Ribose chemical synthesis, Spliceosomes chemistry
- Abstract
Sequencing-based profiling of ribose methylations is a new approach that allows for experiments addressing dynamic changes on a large scale. Here, we apply such a method to spliceosomal snRNAs present in human whole cell RNA. Analysis of solid tissue samples confirmed all previously known sites and demonstrated close to full methylation at almost all sites. Methylation changes were revealed in biological experimental settings, using T cell activation as an example, and in the T cell leukemia model, Jurkat cells. Such changes could impact the dynamics of snRNA interactions during the spliceosome cycle and affect mRNA splicing efficiency and splicing patterns.
- Published
- 2017
- Full Text
- View/download PDF
461. Immunological, chemical and clinical aspects of exposure to mixtures of contact allergens.
- Author
-
Bonefeld CM, Geisler C, Gimenéz-Arnau E, Lepoittevin JP, Uter W, and Johansen JD
- Subjects
- Allergens immunology, Humans, Perfume adverse effects, Allergens adverse effects, Dermatitis, Allergic Contact immunology
- Abstract
Allergic contact dermatitis is one of the most frequent forms of skin inflammation. Very often, we are exposed to mixtures of allergens with varying potencies, doses/areas, and exposure times. Therefore, improved knowledge about immune responses to combinations of contact allergens is highly relevant. In this article, we provide a general introduction to immune responses to contact allergens, and discuss the literature concerning immune responses to mixtures of allergens. According to the existing evidence, increased responses are induced following sensitization with combinations of allergens as compared with single allergens. The response to a mixture of allergens can be both additive and synergistic, depending on the dose and combination of allergens. Importantly, sensitization with combinations of either fragrance allergens or metal salts can result in increased challenge responses to specific allergens within the mixture. Taken together, the immune responses to mixtures of allergens are complex, and further studies are required to obtain the necessary knowledge to improve consumer safety., (© 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
- Published
- 2017
- Full Text
- View/download PDF
462. A novel BLK-induced tumor model.
- Author
-
Petersen DL, Berthelsen J, Willerslev-Olsen A, Fredholm S, Dabelsteen S, Bonefeld CM, Geisler C, and Woetmann A
- Subjects
- Animals, B-Lymphocytes pathology, Cell Line, Tumor, Disease Models, Animal, Gene Expression Regulation, Neoplastic, Humans, Lymphoma, T-Cell, Cutaneous pathology, Mice, Proto-Oncogene Mas, Signal Transduction, Xenograft Model Antitumor Assays, src-Family Kinases biosynthesis, Carcinogenesis genetics, Lymphocyte Activation genetics, Lymphoma, T-Cell, Cutaneous genetics, src-Family Kinases genetics
- Abstract
B-lymphoid tyrosine kinase (BLK) is a non-receptor tyrosine kinase belonging to the SRC family kinases. BLK is known to be functionally involved in B-cell receptor signaling and B-cell development. New evidence suggests that B-lymphoid tyrosine kinase is ectopically expressed and is a putative oncogene in cutaneous T-cell lymphoma and other T-cell malignancies. However, little is known about the role of BLK in lymphomagenesis, and the oncogenic function seems to depend on the cellular context. Importantly, BLK is also ectopically expressed in other hematological and multiple non-hematological malignancies including breast, kidney, and lung cancers, suggesting that BLK could be a new potential target for therapy. Here, we studied the oncogenic potential of human BLK. We found that engrafted Ba/F3 cells stably expressing constitutive active human BLK formed tumors in mice, whereas neither Ba/F3 cells expressing wild type BLK nor non-transfected Ba/F3 cells did. Inhibition of BLK with the clinical grade and broadly reacting SRC family kinase inhibitor dasatinib inhibited growth of BLK-induced tumors. In conclusion, our study provides evidence that human BLK is a true proto-oncogene capable of inducing tumors, and we demonstrate a novel BLK activity-dependent tumor model suitable for studies of BLK-driven lymphomagenesis and screening of novel BLK inhibitors in vivo.
- Published
- 2017
- Full Text
- View/download PDF
463. Vitamin D Counteracts Mycobacterium tuberculosis -Induced Cathelicidin Downregulation in Dendritic Cells and Allows Th1 Differentiation and IFNγ Secretion.
- Author
-
Rode AKO, Kongsbak M, Hansen MM, Lopez DV, Levring TB, Woetmann A, Ødum N, Bonefeld CM, and Geisler C
- Abstract
Tuberculosis (TB) presents a serious health problem with approximately one-third of the world's population infected with Mycobacterium tuberculosis in a latent state. Experience from the pre-antibiotic era and more recent clinical studies have established a beneficial role of sunlight and vitamin D in patients with TB. At the same time, experimental data have shown that Th1 cells through production of IFNγ are crucial for cathelicidin release by macrophages, bacterial killing, and containment of M. tuberculosis in granulomas. Paradoxically, vitamin D has repeatedly been ascribed an immune-suppressive function inhibiting Th1 differentiation and production of IFNγ in T cells. The aim of this study was to investigate this apparent paradox. We studied naïve human CD4
+ T cells activated either with CD3 and CD28 antibodies or with allogeneic dendritic cells (DC) stimulated with heat-killed M. tuberculosis (HKMT) or purified toll-like receptor (TLR) ligands. We show that vitamin D does not block differentiation of human CD4+ T cells to Th1 cells and that interleukin (IL)-12 partially counteracts vitamin D-mediated inhibition of IFNγ production promoting production of equal amounts of IFNγ in Th1 cells in the presence of vitamin D as in T cells activated in the absence of vitamin D and IL-12. Furthermore, we show that HKMT and TLR2 ligands strongly downregulate cathelicidin expression in DC and that vitamin D counteracts this by upregulating cathelicidin expression. In conclusion, we demonstrate that vitamin D counteracts M. tuberculosis -induced cathelicidin downregulation and allows Th1 differentiation and IFNγ secretion.- Published
- 2017
- Full Text
- View/download PDF
464. Rapid allergen-induced interleukin-17 and interferon-γ secretion by skin-resident memory CD8 + T cells.
- Author
-
Schmidt JD, Ahlström MG, Johansen JD, Dyring-Andersen B, Agerbeck C, Nielsen MM, Poulsen SS, Woetmann A, Ødum N, Thomsen AR, Geisler C, and Bonefeld CM
- Subjects
- Animals, Humans, Mice, CD8-Positive T-Lymphocytes immunology, Dermatitis, Contact immunology, Immunologic Memory, Interferon-gamma biosynthesis, Interleukin-17 biosynthesis, Skin immunology
- Abstract
Background: Skin-resident memory T (T
RM ) cells are associated with immunological memory in the skin. Whether immunological memory responses to allergens in the skin are solely localized to previously allergen-exposed sites or are present globally in the skin is not clear. Furthermore, the mechanisms whereby TRM cells induce rapid recall responses need further investigation., Objectives: To study whether contact allergens induce local and/or global memory, and to determine the mechanisms involved in memory responses in the skin., Methods: To address these questions, we analysed responses to contact allergens in mice and humans sensitized to 2,4-dinitrofluorobenzene and nickel, respectively., Results: Challenge responses in both mice and humans were dramatically increased at sites previously exposed to allergens as compared with previously unexposed sites. Importantly, the magnitude of the challenge response correlated with the epidermal accumulation of interleukin (IL)-17A-producing and interferon (IFN)-γ-producing TRM cells. Moreover, IL-17A and IFN-γ enhanced allergen-induced IL-1β production in keratinocytes., Conclusions: We show that sensitization with contact allergens induces a strong, long-lasting local memory and a weaker, temporary global immunological memory response to the allergen that is mediated by IL-17A-producing and IFN-γ-producing CD8+ TRM cells., (© 2016 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)- Published
- 2017
- Full Text
- View/download PDF
465. The role of innate lymphoid cells in healthy and inflamed skin.
- Author
-
Bonefeld CM and Geisler C
- Subjects
- Animals, Dermatitis, Allergic Contact etiology, Dermatitis, Allergic Contact metabolism, Dermatitis, Allergic Contact pathology, Dermatitis, Atopic etiology, Dermatitis, Atopic metabolism, Dermatitis, Atopic pathology, Filaggrin Proteins, Humans, Intermediate Filament Proteins genetics, Intermediate Filament Proteins metabolism, Lymphocyte Subsets cytology, Psoriasis etiology, Psoriasis metabolism, Psoriasis pathology, Skin cytology, Skin immunology, Skin metabolism, Skin pathology, Wound Healing genetics, Wound Healing immunology, Dermatitis etiology, Dermatitis metabolism, Disease Susceptibility, Immunity, Innate, Lymphocyte Subsets immunology, Lymphocyte Subsets metabolism
- Abstract
The skin constitutes the interface between the organism and the environment, and it protects the body from harmful substances in the environment via physical, chemical and immunological barriers. The immunological barrier of the skin comprises both cells from the innate and the adaptive immune system. During the last years, it has become clear that innate lymphoid cells play a role in homeostasis and inflammation of the skin in humans and mice. In this review, we will discuss the role of innate lymphoid cells in healthy and inflamed skin with special focus on their role in atopic dermatitis., (Copyright © 2016 European Federation of Immunological Societies. Published by Elsevier B.V. All rights reserved.)
- Published
- 2016
- Full Text
- View/download PDF
466. The major diversification of Vγ1.1 + and Vγ2 + thymocytes in mice occurs after commitment to the γδ T-cell lineage.
- Author
-
Buus TB, Geisler C, and Lauritsen JP
- Subjects
- 5'-Nucleotidase genetics, Animals, CD24 Antigen metabolism, Cell Differentiation, Cell Lineage, Cells, Cultured, Female, Mice, Mice, Inbred C57BL, Mice, Knockout, 5'-Nucleotidase metabolism, Receptors, Antigen, T-Cell, gamma-delta metabolism, T-Lymphocyte Subsets physiology, T-Lymphocytes physiology, Thymus Gland immunology
- Abstract
γδ T cells are a heterogeneous cell population with different subsets playing specialized and often opposing roles during immune responses. A key question is whether γδ thymocytes are determined for their effector function already at an early stage, before their commitment to the γδ T-cell lineage, or are instructed during their later development. Here, we show that the adult Vγ1.1
+ and Vγ2+ γδ T-cell subsets both go through a CD73+ CD24+ development stage, and that the gene regulation involved in lineage commitment is shared by both subsets. We demonstrate that the major subset diversification first occurs after the cells have committed to the γδ T-cell lineage, strongly supporting an instructive model for functional programming of γδ T cells. In conclusion, we show that the two major adult γδ T-cell subsets in mice develop through a shared pathway utilizing similar cellular machinery and that they diverge after the CD24+ CD73+ maturity stage., (© 2016 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)- Published
- 2016
- Full Text
- View/download PDF
467. STAT5 induces miR-21 expression in cutaneous T cell lymphoma.
- Author
-
Lindahl LM, Fredholm S, Joseph C, Nielsen BS, Jønson L, Willerslev-Olsen A, Gluud M, Blümel E, Petersen DL, Sibbesen N, Hu T, Nastasi C, Krejsgaard T, Jæhger D, Persson JL, Mongan N, Wasik MA, Litvinov IV, Sasseville D, Koralov SB, Bonefeld CM, Geisler C, Woetmann A, Ralfkiaer E, Iversen L, and Odum N
- Subjects
- Female, Humans, Lymphoma, T-Cell, Cutaneous genetics, Male, MicroRNAs genetics, STAT5 Transcription Factor genetics, Skin Neoplasms genetics, Gene Expression Regulation, Neoplastic physiology, Lymphoma, T-Cell, Cutaneous metabolism, MicroRNAs biosynthesis, STAT5 Transcription Factor metabolism, Skin Neoplasms metabolism
- Abstract
In cutaneous T cell lymphomas (CTCL), miR-21 is aberrantly expressed in skin and peripheral blood and displays anti-apoptotic properties in malignant T cells. It is, however, unclear exactly which cells express miR-21 and what mechanisms regulate miR-21. Here, we demonstrate miR-21 expression in situ in both malignant and reactive lymphocytes as well as stromal cells. qRT-PCR analysis of 47 patients with mycosis fungoides (MF) and Sezary Syndrome (SS) confirmed an increased miR-21 expression that correlated with progressive disease. In cultured malignant T cells miR-21 expression was inhibited by Tofacitinib (CP-690550), a clinical-grade JAK3 inhibitor. Chromatin immunoprecipitation (ChIP) analysis showed direct binding of STAT5 to the miR-21 promoter. Cytokine starvation ex vivo triggered a decrease in miR-21 expression, whereas IL-2 induced an increased miR-21 expression in primary SS T cells and cultured cytokine-dependent SS cells (SeAx). siRNA-mediated depletion of STAT5 inhibited constitutive- and IL-2-induced miR-21 expression in cytokine-independent and dependent T cell lines, respectively. IL-15 and IL-2 were more potent than IL-21 in inducing miR-21 expression in the cytokine-dependent T cells. In conclusion, we provide first evidence that miR-21 is expressed in situ in CTCL skin lesions, induced by IL-2 and IL-15 cytokines, and is regulated by STAT5 in malignant T cells. Thus, our data provide novel evidence for a pathological role of IL-2Rg cytokines in promoting expression of the oncogenic miR-21 in CTCL., Competing Interests: The authors declare no conflicts of interest.
- Published
- 2016
- Full Text
- View/download PDF
468. Development of interleukin-17-producing Vγ2+ γδ T cells is reduced by ICOS signaling in the thymus.
- Author
-
Buus TB, Schmidt JD, Bonefeld CM, Geisler C, and Lauritsen JP
- Subjects
- Animals, Dinitrofluorobenzene immunology, Dinitrofluorobenzene pharmacology, Flow Cytometry, Inducible T-Cell Co-Stimulator Protein genetics, Inducible T-Cell Co-Stimulator Protein metabolism, Interleukin-17 metabolism, Lymph Nodes immunology, Lymph Nodes metabolism, Mice, Inbred C57BL, Mice, Knockout, Receptors, Antigen, T-Cell, gamma-delta metabolism, Signal Transduction immunology, Skin immunology, Skin metabolism, Spleen immunology, Spleen metabolism, T-Lymphocyte Subsets drug effects, T-Lymphocyte Subsets metabolism, Thymocytes immunology, Thymocytes metabolism, Thymus Gland embryology, Thymus Gland metabolism, Inducible T-Cell Co-Stimulator Protein immunology, Interleukin-17 immunology, Receptors, Antigen, T-Cell, gamma-delta immunology, T-Lymphocyte Subsets immunology, Thymus Gland immunology
- Abstract
Co-stimulation is an integral part of T cell signaling involved in almost all facets of T cell biology. While much is known about co-stimulation in differentiation and function of conventional αβ T cells, less is known about how co-stimulation affects the development and programming of γδ T cells. In this study, we have investigated the role of inducible T cell co-stimulator (ICOS) on the development of γδ T cells. We show that ICOS is expressed by a population of immature Vγ2+CD45RBlow γδ T cells predisposed to interleukin-17 (IL-17) production. We found that treatment with ICOS specific antibodies drastically reduces fetal development of IL-17-producing γδ T cells by agonistic actions, and that ICOS deficient mice have a significant increase in the population of IL-17-producing Vγ2+ γδ T cells in the thymus, spleen, lymph nodes and skin and exhibit exacerbated sensitization responses to 2,4-dinitrofluorobenzene. In conclusion, this study demonstrates that development of IL-17-producing Vγ2+ γδ T cells is reduced by ICOS signaling in the thymus.
- Published
- 2016
- Full Text
- View/download PDF
469. The Expression of IL-21 Is Promoted by MEKK4 in Malignant T Cells and Associated with Increased Progression Risk in Cutaneous T-Cell Lymphoma.
- Author
-
Fredholm S, Litvinov IV, Mongan NP, Schiele S, Willerslev-Olsen A, Petersen DL, Krejsgaard T, Sibbesen N, Nastasi C, Bonefeld CM, Persson JL, Straten PT, Andersen MH, Koralov SB, Wasik MM, Geisler C, Sasseville D, Woetmann A, and Ødum N
- Subjects
- Disease Progression, Humans, Inflammation, Interleukins genetics, MAP Kinase Signaling System, Phosphorylation, RNA, Small Interfering metabolism, STAT3 Transcription Factor metabolism, Signal Transduction, Gene Expression Regulation, Neoplastic, Interleukins metabolism, Lymphoma, T-Cell metabolism, MAP Kinase Kinase Kinase 4 metabolism, Skin Neoplasms metabolism, T-Lymphocytes metabolism
- Published
- 2016
- Full Text
- View/download PDF
470. Human CD4+ T cells require exogenous cystine for glutathione and DNA synthesis.
- Author
-
Levring TB, Kongsbak M, Rode AK, Woetmann A, Ødum N, Bonefeld CM, and Geisler C
- Subjects
- CD4-Positive T-Lymphocytes drug effects, CD4-Positive T-Lymphocytes immunology, Glutathione biosynthesis, Humans, Jurkat Cells, Lymphocyte Activation, Ribonucleotide Reductases metabolism, Thioredoxins metabolism, CD4-Positive T-Lymphocytes metabolism, Cystine metabolism, Cystine pharmacology, DNA biosynthesis, Glutathione metabolism
- Abstract
Adaptive immune responses require activation and expansion of antigen-specific T cells. Whereas early T cell activation is independent of exogenous cystine (Cys2), T cell proliferation is dependent of Cys2. However, the exact roles of Cys2 in T cell proliferation still need to be determined. The aim of this study was to elucidate why activated human T cells require exogenous Cys2 in order to proliferate. We activated purified naïve human CD4+ T cells and found that glutathione (GSH) levels and DNA synthesis were dependent on Cys2 and increased in parallel with increasing concentrations of Cys2. Vice-versa, the GSH synthesis inhibitor L-buthionine-sulfoximine (BSO) and inhibition of Cys2 uptake with glutamate inhibited GSH and DNA synthesis in parallel. We further found that thioredoxin (Trx) can partly substitute for GSH during DNA synthesis. Finally, we show that GSH or Trx is required for the activity of ribonucleotide reductase (RNR), the enzyme responsible for generation of the deoxyribonucleotide DNA building blocks. In conclusion, we show that activated human T cells require exogenous Cys2 to proliferate and that this is partly explained by the fact that Cys2 is required for production of GSH, which in turn is required for optimal RNR-mediated deoxyribonucleotide synthesis and DNA replication.
- Published
- 2015
- Full Text
- View/download PDF
471. Jak3, STAT3, and STAT5 inhibit expression of miR-22, a novel tumor suppressor microRNA, in cutaneous T-Cell lymphoma.
- Author
-
Sibbesen NA, Kopp KL, Litvinov IV, Jønson L, Willerslev-Olsen A, Fredholm S, Petersen DL, Nastasi C, Krejsgaard T, Lindahl LM, Gniadecki R, Mongan NP, Sasseville D, Wasik MA, Iversen L, Bonefeld CM, Geisler C, Woetmann A, and Odum N
- Subjects
- Cell Line, Tumor, Genes, Tumor Suppressor, Humans, Janus Kinase 3 antagonists & inhibitors, Janus Kinase 3 genetics, Lymphoma, T-Cell, Cutaneous metabolism, Lymphoma, T-Cell, Cutaneous pathology, MicroRNAs administration & dosage, MicroRNAs biosynthesis, MicroRNAs genetics, Piperidines pharmacology, Protein Kinase Inhibitors pharmacology, Pyrimidines pharmacology, Pyrroles pharmacology, STAT3 Transcription Factor genetics, STAT5 Transcription Factor genetics, Signal Transduction, Skin Neoplasms metabolism, Skin Neoplasms pathology, Transfection, Janus Kinase 3 metabolism, Lymphoma, T-Cell, Cutaneous genetics, MicroRNAs antagonists & inhibitors, STAT3 Transcription Factor metabolism, STAT5 Transcription Factor metabolism, Skin Neoplasms genetics
- Abstract
Aberrant activation of Janus kinase-3 (Jak3) and its key down-stream effectors, Signal Transducer and Activator of Transcription-3 (STAT3) and STAT5, is a key feature of malignant transformation in cutaneous T-cell lymphoma (CTCL). However, it remains only partially understood how Jak3/STAT activation promotes lymphomagenesis. Recently, non-coding microRNAs (miRNAs) have been implicated in the pathogenesis of this malignancy. Here, we show that (i) malignant T cells display a decreased expression of a tumor suppressor miRNA, miR-22, when compared to non-malignant T cells, (ii) STAT5 binds the promoter of the miR-22 host gene, and (iii) inhibition of Jak3, STAT3, and STAT5 triggers increased expression of pri-miR-22 and miR-22. Curcumin, a nutrient with anti-Jak3 activity and histone deacetylase inhibitors (HDACi) also trigger increased expression of pri-miR-22 and miR-22. Transfection of malignant T cells with recombinant miR-22 inhibits the expression of validated miR-22 targets including NCoA1, a transcriptional co-activator in others cancers, as well as HDAC6, MAX, MYCBP, PTEN, and CDK2, which have all been implicated in CTCL pathogenesis. In conclusion, we provide the first evidence that de-regulated Jak3/STAT3/STAT5 signalling in CTCL cells represses the expression of the gene encoding miR-22, a novel tumor suppressor miRNA.
- Published
- 2015
- Full Text
- View/download PDF
472. Malignant T cells express lymphotoxin α and drive endothelial activation in cutaneous T cell lymphoma.
- Author
-
Lauenborg B, Christensen L, Ralfkiaer U, Kopp KL, Jønson L, Dabelsteen S, Bonefeld CM, Geisler C, Gjerdrum LM, Zhang Q, Wasik MA, Ralfkiaer E, Ødum N, and Woetmann A
- Subjects
- Adult, Aged, Aged, 80 and over, Binding Sites genetics, DNA-Binding Proteins metabolism, Endothelial Cells metabolism, Female, Human Umbilical Vein Endothelial Cells, Humans, Janus Kinase 3 genetics, Janus Kinase 3 metabolism, Lymphatic Metastasis pathology, Male, Middle Aged, NF-kappa B metabolism, Neovascularization, Pathologic pathology, Promoter Regions, Genetic genetics, RNA Interference, RNA, Small Interfering, Receptors, Tumor Necrosis Factor, Type II metabolism, STAT5 Transcription Factor genetics, STAT5 Transcription Factor metabolism, T-Lymphocytes pathology, Tumor Cells, Cultured, Tumor Suppressor Proteins genetics, Tumor Suppressor Proteins metabolism, Interleukin-6 metabolism, Lymphoma, T-Cell, Cutaneous pathology, Lymphotoxin-alpha metabolism, Skin Neoplasms pathology, Vascular Endothelial Growth Factor A metabolism
- Abstract
Lymphotoxin α (LTα) plays a key role in the formation of lymphatic vasculature and secondary lymphoid structures. Cutaneous T cell lymphoma (CTCL) is the most common primary lymphoma of the skin and in advanced stages, malignant T cells spreads through the lymphatic to regional lymph nodes to internal organs and blood. Yet, little is known about the mechanism of the CTCL dissemination. Here, we show that CTCL cells express LTα in situ and that LTα expression is driven by aberrantly activated JAK3/STAT5 pathway. Importantly, via TNF receptor 2, LTα functions as an autocrine factor by stimulating expression of IL-6 in the malignant cells. LTα and IL-6, together with VEGF promote angiogenesis by inducing endothelial cell sprouting and tube formation. Thus, we propose that LTα plays a role in malignant angiogenesis and disease progression in CTCL and may serve as a therapeutic target in this disease.
- Published
- 2015
- Full Text
- View/download PDF
473. Ectopic expression of a novel CD22 splice-variant regulates survival and proliferation in malignant T cells from cutaneous T cell lymphoma (CTCL) patients.
- Author
-
Bagdonaite I, Wandall HH, Litvinov IV, Nastasi C, Becker JC, Dabelsteen S, Geisler C, Bonefeld CM, Zhang Q, Wasik MA, Zhou Y, Sasseville D, Ødum N, and Woetmann A
- Subjects
- Animals, Cell Line, Tumor, Humans, Lymphocyte Activation, Lymphoma, T-Cell, Cutaneous immunology, Mice, Protein Isoforms, RNA Splicing, Sialic Acid Binding Ig-like Lectin 2 genetics, T-Lymphocytes immunology, Transfection, Lymphoma, T-Cell, Cutaneous genetics, Lymphoma, T-Cell, Cutaneous metabolism, Sialic Acid Binding Ig-like Lectin 2 biosynthesis, T-Lymphocytes metabolism
- Abstract
CD22 is a member of the Sialic acid-binding Ig-like lectin (Siglec) family of lectins described to be exclusively present in B lymphocytes and B cell-derived neoplasms. Here, we describe a novel splice form of CD22 (designated CD22âN), which lacks the N-terminal domain as demonstrated by exon-specific RT-PCR and differential recognition by anti-CD22 antibodies. Importantly, CD22âN mRNA is expressed in skin lesions from 39 out of 60 patients with cutaneous T cell lymphoma (CTCL), whereas few patients (6 out of 60) expresses full-length, wild type CD22 (CD22wt). In addition, IHC staining of tumor biopsies confirmed the expression of CD22 in CD4+ T cells. Moreover, four out of four malignant T cell lines express CD22: Two cell lines express CD22âN (MyLa2059 and PB2B) and two express CD22wt (MAC-1 and MAC-2A). siRNA-mediated silencing of CD22 impairs proliferation and survival of malignant T cells, demonstrating a functional role for both CD22âN and CD22wt in these cells.In conclusion, we provide the first evidence for an ectopic expression of CD22 and a novel splice variant regulating malignant proliferation and survival in CTCL. Analysis of expression and function of CD22 in cutaneous lymphomas may form the basis for development of novel targeted therapies for our patients.
- Published
- 2015
- Full Text
- View/download PDF
474. Midline 1 controls polarization and migration of murine cytotoxic T cells.
- Author
-
Boding L, Hansen AK, Nielsen MM, Meroni G, Braunstein TH, Woetmann A, Ødum N, Bonefeld CM, and Geisler C
- Abstract
Midline 1 (MID1) is a microtubule-associated ubiquitin ligase that regulates protein phosphatase 2 A levels. Loss-of-function mutations in MID1 lead to the human X-linked Opitz G/BBB (OS) syndrome characterized by defective midline development during embryogenesis. We have recently shown that MID1 is strongly up-regulated in murine cytotoxic T lymphocytes (CTLs), and that it has a significant impact on exocytosis of lytic granules and the killing capacity of CTLs. The aims of the present study were to determine the localization of MID1 in migrating CTLs, and to investigate whether MID1 affects CTL polarization and migration. We found that MID1 mainly localizes to the uropod of migrating CTLs and that it has a substantial impact on CTL polarization and migration in vitro. Furthermore, analysis of contact hypersensitivity responses supported that MID1 controls effector functions of CTLs in hapten-challenged skin in vivo. These results provide significant new knowledge on the role of MID1 in CTL biology.
- Published
- 2014
- Full Text
- View/download PDF
475. MicroRNA expression in early mycosis fungoides is distinctly different from atopic dermatitis and advanced cutaneous T-cell lymphoma.
- Author
-
Ralfkiaer U, Lindahl LM, Litman T, Gjerdrum LM, Ahler CB, Gniadecki R, Marstrand T, Fredholm S, Iversen L, Wasik MA, Bonefeld CM, Geisler C, Krejsgaard T, Glue C, Røpke MA, Woetmann A, Skov L, Grønbæk K, and Odum N
- Subjects
- Biomarkers, Tumor genetics, Dermatitis, Atopic pathology, Disease Progression, Humans, Lymphoma, T-Cell, Cutaneous pathology, MicroRNAs biosynthesis, Mycosis Fungoides pathology, Polymerase Chain Reaction, Skin Neoplasms pathology, Th2 Cells immunology, Dermatitis, Atopic genetics, Lymphoma, T-Cell, Cutaneous genetics, MicroRNAs genetics, Mycosis Fungoides genetics, Skin Neoplasms genetics
- Abstract
Mycosis fungoides (MF) is the most common variant of cutaneous T-cell lymphoma (CTCL). MF is characterized by chronic inflammation dominated by cluster of differentiation 4-positive (CD4(+)) T-cells and T helper 2 cytokines, and as the malignant T-cell clone is initially elusive, early diagnosis is often impossible. MF usually takes an indolent course, but for unknown reasons may turn into an aggressive disease with a poor prognosis. Herein, we used a global quantitative real-time polymerase chain reaction platform to study microRNA (miR) expression in patients with early MF (n=13), more advanced CTCL (n=42), and atopic dermatitis (AD, n=20). Thirty-eight miRs were differentially expressed (≥2-fold) in early MF vs. AD and 36 in early MF vs. more advanced disease. miRs that distinguish early MF from AD included both up-regulated (miR-155, miR-146a, 146b-5p, miR-342-3p, let-7i*) and down-regulated (miR-203, miR-205) miRs previously implicated in advanced CTCL. When comparing early MF to more advanced CTCL, additional miRs were significantly up-regulated including miRs which are part of the oncogenic miR-17/92, 106b/25 and 106a/363 clusters. In 16 patients for whom detailed follow-up data were available, 72 miRs were found differentially expressed between patients with progressive vs. those with non-progressive disease, again including miRs with a known relevance for lymphomagenesis, e.g. miR-155, miR-21, let-7i, miR-16, miR-142-3p, miR-146b-5p, miR-92a, miR-93 and miR-106a. In conclusion, we showed that early MF and AD display very different miR profiles despite their clinical, histological, and immunological similarities. During progression, an additional set of miRs becomes deregulated, suggesting their role in disease progression. These data suggest that miR profiling in CTCL may be a key to improving both diagnosis and risk prediction., (Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)
- Published
- 2014
476. STAT3 activation and infiltration of eosinophil granulocytes in mycosis fungoides.
- Author
-
Fredholm S, Gjerdrum LM, Willerslev-Olsen A, Petersen DL, Nielsen IØ, Kauczok CS, Wobser M, Ralfkiaer U, Bonefeld CM, Wasik MA, Krejsgaard T, Geisler C, Ralfkiaer E, Gniadecki R, Woetmann A, and Odum N
- Subjects
- Biopsy, Cell Line, Tumor, Gene Knockout Techniques, HMGB1 Protein genetics, HMGB1 Protein metabolism, Humans, Immunohistochemistry, Interleukin-5 genetics, Interleukin-5 metabolism, Mycosis Fungoides genetics, Mycosis Fungoides immunology, RNA Interference, STAT3 Transcription Factor genetics, T-Lymphocytes immunology, T-Lymphocytes metabolism, T-Lymphocytes pathology, Eosinophils pathology, Mycosis Fungoides metabolism, Mycosis Fungoides pathology, STAT3 Transcription Factor metabolism
- Abstract
Eosinophil granulocytes have been implicated in anticancer immunity but recent data indicate that eosinophils can also promote cancer. Herein, we studied eosinophils in skin lesions from 43 patients with mycosis fungoides (MF). The presence of eosinophils correlated with disease stage: 78% of patients with advanced disease displayed eosinophil infiltration, whereas this was only seen in 11% of patients with patches (p<0.01), and in 48% of those with plaque disease. Importantly, 72% of patients with positive staining for phospho-signal-transducer-and-activator-of-transcription (pY-STAT3) in malignant T-cells also stained positively for eosinophils, whereas this was only observed in 28% of pY-STAT3-negative patients (p<0.01). Notably, malignant T-cells expressed eosinophilic activation and trafficking factors: High-mobility group BOX-1 protein (HMGB1) and interleukin 5 (IL5). STAT3 siRNA profoundly inhibited IL5 but not HMGB1 expression. In conclusion, these data suggest that malignant T-cells orchestrate accumulation and activation of eosinophils supporting the notion of STAT3 being a putative target for therapy., (Copyright© 2014 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)
- Published
- 2014
477. Midline 1 directs lytic granule exocytosis and cytotoxicity of mouse killer T cells.
- Author
-
Boding L, Hansen AK, Meroni G, Johansen BB, Braunstein TH, Bonefeld CM, Kongsbak M, Jensen BA, Woetmann A, Thomsen AR, Odum N, von Essen MR, and Geisler C
- Subjects
- Animals, Blotting, Western, Flow Cytometry, Mice, Mice, Knockout, Mice, Transgenic, Proteins metabolism, Reverse Transcriptase Polymerase Chain Reaction, Secretory Vesicles immunology, T-Lymphocytes, Cytotoxic metabolism, Ubiquitin-Protein Ligases, Cytotoxicity, Immunologic immunology, Exocytosis physiology, Proteins immunology, Secretory Vesicles metabolism, T-Lymphocytes, Cytotoxic immunology
- Abstract
Midline 1 (MID1) is a microtubule-associated ubiquitin ligase that regulates protein phosphatase 2A activity. Loss-of-function mutations in MID1 lead to the X-linked Opitz G/BBB syndrome characterized by defective midline development during embryogenesis. Here, we show that MID1 is strongly upregulated in murine cytotoxic lymphocytes (CTLs), and that it controls TCR signaling, centrosome trafficking, and exocytosis of lytic granules. In accordance, we find that the killing capacity of MID1(-/-) CTLs is impaired. Transfection of MID1 into MID1(-/-) CTLs completely rescued lytic granule exocytosis, and vice versa, knockdown of MID1 inhibited exocytosis of lytic granules in WT CTLs, cementing a central role for MID1 in the regulation of granule exocytosis. Thus, MID1 orchestrates multiple events in CTL responses, adding a novel level of regulation to CTL activation and cytotoxicity., (© 2014 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)
- Published
- 2014
- Full Text
- View/download PDF
478. Vitamin D up-regulates the vitamin D receptor by protecting it from proteasomal degradation in human CD4+ T cells.
- Author
-
Kongsbak M, von Essen MR, Boding L, Levring TB, Schjerling P, Lauritsen JP, Woetmann A, Ødum N, Bonefeld CM, and Geisler C
- Subjects
- Antifungal Agents pharmacology, CD4-Positive T-Lymphocytes drug effects, CD4-Positive T-Lymphocytes metabolism, Cells, Cultured, Cytochrome P-450 CYP3A Inhibitors pharmacology, Fatty Acids, Unsaturated pharmacology, Humans, Ketoconazole pharmacology, Lymphocyte Activation, Proteasome Endopeptidase Complex immunology, Proteasome Inhibitors pharmacology, Protein Transport drug effects, Proteolysis drug effects, Receptors, Calcitriol genetics, Receptors, Calcitriol immunology, Up-Regulation drug effects, CD4 Antigens immunology, CD4-Positive T-Lymphocytes immunology, Calcitriol immunology, Proteasome Endopeptidase Complex metabolism, Receptors, Calcitriol metabolism
- Abstract
The active form of vitamin D3, 1,25(OH)2D3, has significant immunomodulatory properties and is an important determinant in the differentiation of CD4+ effector T cells. The biological actions of 1,25(OH)2D3 are mediated by the vitamin D receptor (VDR) and are believed to correlate with the VDR protein expression level in a given cell. The aim of this study was to determine if and how 1,25(OH)2D3 by itself regulates VDR expression in human CD4+ T cells. We found that activated CD4+ T cells have the capacity to convert the inactive 25(OH)D3 to the active 1,25(OH)2D3 that subsequently up-regulates VDR protein expression approximately 2-fold. 1,25(OH)2D3 does not increase VDR mRNA expression but increases the half-life of the VDR protein in activated CD4+ T cells. Furthermore, 1,25(OH)2D3 induces a significant intracellular redistribution of the VDR. We show that 1,25(OH)2D3 stabilizes the VDR by protecting it from proteasomal degradation. Finally, we demonstrate that proteasome inhibition leads to up-regulation of VDR protein expression and increases 1,25(OH)2D3-induced gene activation. In conclusion, our study shows that activated CD4+ T cells can produce 1,25(OH)2D3, and that 1,25(OH)2D3 induces a 2-fold up-regulation of the VDR protein expression in activated CD4+ T cells by protecting the VDR against proteasomal degradation.
- Published
- 2014
- Full Text
- View/download PDF
479. An immune response study of oakmoss absolute and its constituents atranol and chloroatranol.
- Author
-
Bonefeld CM, Nielsen MM, Gimenéz-Arnau E, Lang M, Vennegaard MT, Geisler C, Johansen JD, and Lepoittevin JP
- Subjects
- Animals, Antigens, CD19 immunology, B-Lymphocytes immunology, CD4-Positive T-Lymphocytes immunology, CD8-Positive T-Lymphocytes immunology, Cell Line, Cell Proliferation, Interleukin-18 immunology, Interleukin-1beta immunology, Keratinocytes, Mice, Mice, Inbred CBA, Patch Tests, Tumor Necrosis Factor-alpha immunology, Benzaldehydes immunology, Dermatitis, Allergic Contact immunology, Resins, Plant chemistry, Terpenes chemistry, Terpenes immunology
- Abstract
Background: Atranol and chloroatranol are the main allergens of oakmoss absolute. However, the immune responses induced by these substances are poorly characterized., Objectives: To characterize immune responses induced by atranol, chloroatranol and oakmoss absolute in mice., Methods: Mice were sensitized and challenged with various concentrations of atranol, chloroatranol, and oakmoss absolute. The immune responses were analysed as B cell infiltration, T cell proliferation in the draining lymph nodes, and expression of interleukin (IL)-18, IL-1β and tumour necrosis factor-α in skin. The cytotoxicity of atranol and chloroatranol against keratinocytes was determined., Results: Sensitization experiments showed that atranol, chloroatranol and oakmoss induced sensitization when applied in high concentrations. Challenge experiments showed that even low concentrations of atranol and chloroatranol induced sensitization. In parallel, atranol and chloroatranol elicited challenge reactions following sensitization with oakmoss. The magnitude of the immune response to the three allergens increased in the following order: atranol, chloroatranol, and oakmoss. The expression of proinflammatory cytokines was induced by chloroatranol and oakmoss, but not by atranol. Chloroatranol was found to be more cytotoxic than atranol against keratinocytes., Conclusions: Atranol and chloroatranol can elicit both sensitization and challenge reactions, but the mixture of allergens in oakmoss absolute is more potent than atranol and chloroatranol alone., (© 2014 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
- Published
- 2014
- Full Text
- View/download PDF
480. The vitamin d receptor and T cell function.
- Author
-
Kongsbak M, Levring TB, Geisler C, and von Essen MR
- Abstract
The vitamin D receptor (VDR) is a nuclear, ligand-dependent transcription factor that in complex with hormonally active vitamin D, 1,25(OH)2D3, regulates the expression of more than 900 genes involved in a wide array of physiological functions. The impact of 1,25(OH)2D3-VDR signaling on immune function has been the focus of many recent studies as a link between 1,25(OH)2D3 and susceptibility to various infections and to development of a variety of inflammatory diseases has been suggested. It is also becoming increasingly clear that microbes slow down immune reactivity by dysregulating the VDR ultimately to increase their chance of survival. Immune modulatory therapies that enhance VDR expression and activity are therefore considered in the clinic today to a greater extent. As T cells are of great importance for both protective immunity and development of inflammatory diseases a variety of studies have been engaged investigating the impact of VDR expression in T cells and found that VDR expression and activity plays an important role in both T cell development, differentiation and effector function. In this review we will analyze current knowledge of VDR regulation and function in T cells and discuss its importance for immune activity.
- Published
- 2013
- Full Text
- View/download PDF
481. PKC-θ exists in an oxidized inactive form in naive human T cells.
- Author
-
von Essen MR, Kongsbak M, Levring TB, Hansen AK, Boding L, Lauritsen JP, Woetmann A, Baier G, Ødum N, Bonefeld CM, and Geisler C
- Subjects
- Cells, Cultured, Glutathione metabolism, Humans, Lymphocyte Activation, Oxidation-Reduction, Protein Kinase C-theta, Protein Transport, Signal Transduction, Cell Membrane metabolism, Isoenzymes metabolism, Protein Kinase C metabolism, T-Lymphocyte Subsets immunology, T-Lymphocytes immunology
- Abstract
PKC-θ plays a central role in TCR-induced IL-2 production and T-cell proliferation. The aim of the present study was to analyse how PKC-θ is regulated in human T cells during T-cell activation and differentiation. We show that PKC-θ is found in a high-molecular disulfide-linked complex in naïve T cells, and that PKC-θ most likely is inactive in this form. In parallel with the accumulation of the major redox regulators, glutathione and thioredoxin, PKC-θ is gradually reduced to the 82 kDa active form during T-cell activation. We demonstrate that PKC-θ is recruited to the plasma membrane in the disulfide-linked form in naïve T cells, and that activation of PKC-θ is redox dependent and requires de novo synthesis of glutathione. This is the first study that shows that the activity of PKC-θ is regulated by the intracellular redox state, and that PKC-θ is recruited to the plasma membrane in an inactive form in naïve T cells. Our observations underscore the existence of major differences in TCR signaling in naïve versus primed T cells., (© 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)
- Published
- 2013
- Full Text
- View/download PDF
482. CD4(+) T cells producing interleukin (IL)-17, IL-22 and interferon-γ are major effector T cells in nickel allergy.
- Author
-
Dyring-Andersen B, Skov L, Løvendorf MB, Bzorek M, Søndergaard K, Lauritsen JP, Dabelsteen S, Geisler C, and Bonefeld CM
- Subjects
- Biomarkers metabolism, Biopsy, CD8-Positive T-Lymphocytes metabolism, Case-Control Studies, Dermatitis, Allergic Contact etiology, Dermatitis, Allergic Contact pathology, Flow Cytometry, Humans, Immunohistochemistry, Lymphocyte Count, Nickel adverse effects, Skin immunology, Skin metabolism, Skin pathology, T-Lymphocyte Subsets metabolism, Interleukin-22, CD4-Positive T-Lymphocytes metabolism, Dermatitis, Allergic Contact immunology, Interferon-gamma metabolism, Interleukin-17 metabolism, Interleukins metabolism, Nickel immunology
- Abstract
Background: It has been suggested that interleukin (IL)-17 and IL-22 play important roles in the elicitation of human allergic contact dermatitis; however, the frequencies of T cell subtypes producing IL-17 and IL-22 in human allergic contact dermatitis are unknown., Objectives: To determine the frequencies of CD4(+) , CD8(+) and γδ T cells producing IL-17, IL-22 and interferon (IFN)-γ in the blood and skin from nickel-allergic patients., Patients/materials/methods: Blood samples were collected from 14 patients and 17 controls, and analysed by flow cytometry. Biopsies were taken from 5 patients and 6 controls, and analysed by immunohistochemistry and flow cytometry of skin lymphocytes., Results: We found an increased frequency of γδ T cells in the blood, but no differences in the distribution of cytokine-producing CLA(+) T cell subtypes in nickel-allergic patients as compared with controls. In nickel-allergic patients, there was massive cellular infiltration dominated by CD4(+) T cells producing IL-17, IL-22 and IFN-γ in nickel-challenged skin but not in vehicle-challenged skin., Conclusion: CD4(+) T cells producing IL-17, IL-22 and IFN-γ are important effector cells in the eczematous reactions of nickel-induced allergic contact dermatitis in humans., (© 2013 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.)
- Published
- 2013
- Full Text
- View/download PDF
483. IL-23 and T(H)17-mediated inflammation in human allergic contact dermatitis.
- Author
-
Larsen JM, Bonefeld CM, Poulsen SS, Geisler C, and Skov L
- Subjects
- Allergens immunology, Cell Proliferation drug effects, Cells, Cultured, Dermatitis, Allergic Contact metabolism, Humans, Inflammation metabolism, Interleukin-12 immunology, Interleukin-12 metabolism, Interleukin-17 metabolism, Interleukin-23 biosynthesis, Interleukin-23 pharmacology, Interleukins immunology, Interleukins metabolism, Keratinocytes metabolism, Nickel immunology, Receptors, CCR6 immunology, Receptors, CCR6 metabolism, Receptors, Interleukin immunology, Receptors, Interleukin metabolism, T-Lymphocytes, Helper-Inducer drug effects, T-Lymphocytes, Helper-Inducer metabolism, Interleukin-22, Dermatitis, Allergic Contact immunology, Inflammation immunology, Interleukin-17 immunology, Interleukin-23 immunology, Keratinocytes immunology, T-Lymphocytes, Helper-Inducer immunology
- Abstract
Background: IL-17-producing T(H) (T(H)17) cells are key mediators of chronic inflammation in mice. Recent studies have implicated T(H)17-mediated inflammation in the pathogenesis of human autoimmune diseases; however, the involvement of T(H)17 cells in allergic disorders remains largely elusive., Objective: To investigate T(H)17-mediated inflammation in human beings with allergic contact dermatitis; in particular, the innate response of keratinocytes to contact allergen, the induction of allergen-specific T(H)17 cells, and the presence of T(H)17-related effector cells in inflamed skin., Methods: Human keratinocytes were stimulated with nickel in vitro followed by measurements of IL-23 and IL-12 production by quantitative PCR and ELISA. Allergen-specific memory T cells from the blood of individuals with nickel allergy and healthy controls were identified and characterized by using a short-term ex vivo assay. Nickel patch test lesions and normal skin were analyzed for the expression of T(H)17-related cells and molecules by using immunohistochemistry., Results: Keratinocytes were found to produce IL-23, but no detectable IL-12, in a response to nickel stimulation. Memory T cells isolated from peripheral blood of individuals with nickel allergy, but not healthy controls, contained T(H)17 and T(H)1 cells proliferating in response to nickel-pulsed DCs. Inflamed skin of nickel-challenged allergic individuals contained infiltrating neutrophils and cells expressing IL-17, IL-22, CCR6, and IL-22R., Conclusion: Our results demonstrate the involvement of T(H)17-mediated immunopathology in human allergic contact dermatitis, including both innate and adaptive immune responses to contact allergens.
- Published
- 2009
- Full Text
- View/download PDF
484. TCR down-regulation controls virus-specific CD8+ T cell responses.
- Author
-
Bonefeld CM, Haks M, Nielsen B, von Essen M, Boding L, Hansen AK, Larsen JM, Odum N, Krimpenfort P, Kruisbeek A, Christensen JP, Thomsen AR, and Geisler C
- Subjects
- Amino Acid Motifs genetics, Amino Acid Motifs immunology, Animals, Arenaviridae Infections genetics, CD3 Complex genetics, Mice, Mice, Transgenic, Mutation immunology, Peptides immunology, Proto-Oncogene Proteins c-bcl-2 genetics, Proto-Oncogene Proteins c-bcl-2 immunology, Receptors, Antigen, T-Cell genetics, Rhabdoviridae Infections genetics, Signal Transduction genetics, Signal Transduction immunology, Viral Proteins immunology, Arenaviridae Infections immunology, CD3 Complex immunology, CD8-Positive T-Lymphocytes immunology, Down-Regulation immunology, Lymphocytic choriomeningitis virus immunology, Receptors, Antigen, T-Cell immunology, Rhabdoviridae Infections immunology, Vesiculovirus immunology
- Abstract
The CD3gamma di-leucine-based motif plays a central role in TCR down-regulation. However, little is understood about the role of the CD3gamma di-leucine-based motif in physiological T cell responses. In this study, we show that the expansion in numbers of virus-specific CD8(+) T cells is impaired in mice with a mutated CD3gamma di-leucine-based motif. The CD3gamma mutation did not impair early TCR signaling, nor did it compromise recruitment or proliferation of virus-specific T cells, but it increased the apoptosis rate of the activated T cells by increasing down-regulation of the antiapoptotic molecule Bcl-2. This resulted in a 2-fold reduction in the clonal expansion of virus-specific CD8(+) T cells during the acute phase of vesicular stomatitis virus and lymphocytic choriomeningitis virus infections. These results identify an important role of CD3gamma-mediated TCR down-regulation in virus-specific CD8(+) T cell responses.
- Published
- 2008
- Full Text
- View/download PDF
485. Cellular dynamics in the draining lymph nodes during sensitization and elicitation phases of contact hypersensitivity.
- Author
-
Larsen JM, Geisler C, Nielsen MW, Boding L, Von Essen M, Hansen AK, Skov L, and Bonefeld CM
- Subjects
- Allergens immunology, Animals, Antibodies immunology, Dinitrofluorobenzene immunology, Female, Flow Cytometry, Lymph Nodes cytology, Lymph Nodes immunology, Lymph Nodes physiology, Lymphocyte Activation, Mice, Mice, Inbred C57BL, Oxazolone immunology, T-Lymphocytes physiology, Dermatitis, Allergic Contact immunology, T-Lymphocytes immunology
- Abstract
Background: The different role of various immunological effector cells in contact hypersensitivity (CHS) is receiving increased attention. During the past decade, the involvement of different cell types in CHS has been investigated by the use of antibody-induced depletion of specific subtypes of immunological cells and by studying knockout mice lacking one or more of these immunological cell populations., Objectives: To develop a method for studying the collective cellular dynamics of immune cells in the draining lymph nodes during CHS in intact animals., Patients/methods: Mice were sensitized and/or challenged with 2,4-dinitrofluorobenzene or oxazolone. Using multi-parameter flow cytometry we determined the proliferation, activation state, and absolute number of helper T cells, cytotoxic T cells, B cells, and natural killer cells in the draining lymph nodes., Results: The presented method can be applied to evaluate the effect of different contact allergens on various cell populations of the immune system., Conclusions: Our study support recent findings that several cell types seem to be involved in CHS.
- Published
- 2007
- Full Text
- View/download PDF
486. The adjuvant mechanism of cationic dimethyldioctadecylammonium liposomes.
- Author
-
Korsholm KS, Agger EM, Foged C, Christensen D, Dietrich J, Andersen CS, Geisler C, and Andersen P
- Subjects
- Adsorption, Animals, Antigen Presentation immunology, Antigens metabolism, Cell Differentiation immunology, Cells, Cultured, Dendritic Cells immunology, Female, Mice, Mice, Inbred BALB C, Mice, Transgenic, Ovalbumin immunology, Ovalbumin pharmacokinetics, Quaternary Ammonium Compounds administration & dosage, Adjuvants, Immunologic, Liposomes immunology, Quaternary Ammonium Compounds immunology
- Abstract
Cationic liposomes are being used increasingly as efficient adjuvants for subunit vaccines but their precise mechanism of action is still unknown. Here, we investigated the adjuvant mechanism of cationic liposomes based on the synthetic amphiphile dimethyldioctadecylammonium (DDA). The liposomes did not have an effect on the maturation of murine bone-marrow-derived dendritic cells (BM-DCs) related to the surface expression of major histocompatibility complex (MHC) class II, CD40, CD80 and CD86. We found that ovalbumin (OVA) readily associated with the liposomes (> 90%) when mixed in equal concentrations. This efficient adsorption onto the liposomes led to an enhanced uptake of OVA by BM-DCs as assessed by flow cytometry and confocal fluorescence laser-scanning microscopy. This was an active process, which was arrested at 4 degrees and by an inhibitor of actin-dependent endocytosis, cytochalasin D. In vivo studies confirmed the observed effect because adsorption of OVA onto DDA liposomes enhanced the uptake of the antigen by peritoneal exudate cells after intraperitoneal injection. The liposomes targeted antigen preferentially to antigen-presenting cells because we only observed a minimal uptake by T cells in mixed splenocyte cultures. The adsorption of antigen onto the liposomes increased the efficiency of antigen presentation more than 100 times in a responder assay with MHC class II-restricted OVA-specific T-cell receptor transgenic DO11.10 T cells. Our data therefore suggest that the primary adjuvant mechanism of cationic DDA liposomes is to target the cell membrane of antigen-presenting cells, which subsequently leads to enhanced uptake and presentation of antigen.
- Published
- 2007
- Full Text
- View/download PDF
487. Nonmalignant T cells stimulate growth of T-cell lymphoma cells in the presence of bacterial toxins.
- Author
-
Woetmann A, Lovato P, Eriksen KW, Krejsgaard T, Labuda T, Zhang Q, Mathiesen AM, Geisler C, Svejgaard A, Wasik MA, and Ødum N
- Subjects
- Antigen Presentation drug effects, CD4-Positive T-Lymphocytes pathology, Cell Communication drug effects, Cell Line, Tumor, Coculture Techniques, Enterotoxins pharmacology, Gram-Positive Bacterial Infections immunology, Gram-Positive Bacterial Infections pathology, Gram-Positive Bacterial Infections physiopathology, Histocompatibility Antigens Class II, Humans, Interleukin-2 immunology, Lymphoma, T-Cell, Cutaneous pathology, Lymphoma, T-Cell, Cutaneous physiopathology, Antigen Presentation immunology, CD4-Positive T-Lymphocytes immunology, Cell Communication immunology, Cell Proliferation drug effects, Enterotoxins immunology, Lymphoma, T-Cell, Cutaneous immunology
- Abstract
Bacterial toxins including staphylococcal enterotoxins (SEs) have been implicated in the pathogenesis of cutaneous T-cell lymphomas (CTCLs). Here, we investigate SE-mediated interactions between nonmalignant T cells and malignant T-cell lines established from skin and blood of CTCL patients. The malignant CTCL cells express MHC class II molecules that are high-affinity receptors for SE. Although treatment with SE has no direct effect on the growth of the malignant CTCL cells, the SE-treated CTCL cells induce vigorous proliferation of the SE-responsive nonmalignant T cells. In turn, the nonmalignant T cells enhance proliferation of the malignant cells in an SE- and MHC class II-dependent manner. Furthermore, SE and, in addition, alloantigen presentation by malignant CTCL cells to irradiated nonmalignant CD4(+) T-cell lines also enhance proliferation of the malignant cells. The growth-promoting effect depends on direct cell-cell contact and soluble factors such as interleukin-2. In conclusion, we demonstrate that SE triggers a bidirectional cross talk between nonmalignant T cells and malignant CTCL cells that promotes growth of the malignant cells. This represents a novel mechanism by which infections with SE-producing bacteria may contribute to pathogenesis of CTCL.
- Published
- 2007
- Full Text
- View/download PDF
488. Protein kinase C (PKC) alpha and PKC theta are the major PKC isotypes involved in TCR down-regulation.
- Author
-
von Essen M, Nielsen MW, Bonefeld CM, Boding L, Larsen JM, Leitges M, Baier G, Odum N, and Geisler C
- Subjects
- Amino Acid Motifs, Animals, CD3 Complex physiology, Cell Line, Tumor, Cells, Cultured, Down-Regulation genetics, Humans, Hybridomas, Isoenzymes antagonists & inhibitors, Isoenzymes deficiency, Isoenzymes genetics, Jurkat Cells, Leucine metabolism, Mice, Mice, Knockout, Protein Kinase C antagonists & inhibitors, Protein Kinase C deficiency, Protein Kinase C genetics, Protein Kinase C-alpha deficiency, Protein Kinase C-alpha genetics, Protein Kinase C-theta, RNA, Small Interfering pharmacology, Receptors, Antigen, T-Cell genetics, Signal Transduction genetics, Signal Transduction immunology, Down-Regulation immunology, Isoenzymes physiology, Protein Kinase C physiology, Protein Kinase C-alpha physiology, Receptors, Antigen, T-Cell antagonists & inhibitors, Receptors, Antigen, T-Cell metabolism, T-Lymphocyte Subsets immunology, T-Lymphocyte Subsets metabolism
- Abstract
It is well known that protein kinase C (PKC) plays an important role in regulation of TCR cell surface expression levels. However, eight different PKC isotypes are present in T cells, and to date the particular isotype(s) involved in TCR down-regulation remains to be identified. The aim of this study was to identify the PKC isotype(s) involved in TCR down-regulation and to elucidate the mechanism by which they induce TCR down-regulation. To accomplish this, we studied TCR down-regulation in the human T cell line Jurkat, in primary human T cells, or in the mouse T cell line DO11.10 in which we either overexpressed constitutive active or dominant-negative forms of various PKC isotypes. In addition, we studied TCR down-regulation in PKC knockout mice and by using small interfering RNA-mediated knockdown of specific PKC isotypes. We found that PKCalpha and PKCtheta were the only PKC isotypes able to induce significant TCR down-regulation. Both isotypes mediated TCR down-regulation via the TCR recycling pathway that strictly depends on Ser(126) and the di-leucine-based receptor-sorting motif of the CD3gamma chain. Finally, we found that PKCtheta was mainly implicated in down-regulation of directly engaged TCR, whereas PKCalpha was involved in down-regulation of nonengaged TCR.
- Published
- 2006
- Full Text
- View/download PDF
489. TCR comodulation of nonengaged TCR takes place by a protein kinase C and CD3 gamma di-leucine-based motif-dependent mechanism.
- Author
-
Bonefeld CM, Rasmussen AB, Lauritsen JP, von Essen M, Ødum N, Andersen PS, and Geisler C
- Subjects
- Amino Acid Motifs physiology, Animals, Antibodies, Monoclonal pharmacology, Antibody Specificity, Cell Line, Tumor, Down-Regulation genetics, Down-Regulation immunology, Histocompatibility Antigens Class II physiology, Humans, Jurkat Cells, Ligands, Mice, Peptides pharmacology, Protein Binding immunology, Protein-Tyrosine Kinases physiology, Receptors, Antigen, T-Cell, alpha-beta antagonists & inhibitors, Receptors, Antigen, T-Cell, alpha-beta genetics, T-Lymphocyte Subsets enzymology, T-Lymphocyte Subsets immunology, T-Lymphocyte Subsets metabolism, Transfection, CD3 Complex physiology, Dipeptides physiology, Leucine physiology, Protein Kinase C physiology, Receptors, Antigen, T-Cell, alpha-beta metabolism, Receptors, Antigen, T-Cell, alpha-beta physiology
- Abstract
One of the earliest events following TCR triggering is TCR down-regulation. However, the mechanisms behind TCR down-regulation are still not fully known. Some studies have suggested that only directly triggered TCR are internalized, whereas others studies have indicated that, in addition to triggered receptors, nonengaged TCR are also internalized (comodulated). In this study, we used transfected T cells expressing two different TCR to analyze whether comodulation took place. We show that TCR triggering by anti-TCR mAb and peptide-MHC complexes clearly induced internalization of nonengaged TCR. By using a panel of mAb against the Ti beta chain, we demonstrate that the comodulation kinetics depended on the affinity of the ligand. Thus, high-affinity mAb (K(D) = 2.3 nM) induced a rapid but reversible comodulation, whereas low-affinity mAb (K(D) = 6200 nM) induced a slower but more permanent type of comodulation. Like internalization of engaged TCR, comodulation was dependent on protein tyrosine kinase activity. Finally, we found that in contrast to internalization of engaged TCR, comodulation was highly dependent on protein kinase C activity and the CD3 gamma di-leucine-based motif. Based on these observations, a physiological role of comodulation is proposed and the plausibility of the TCR serial triggering model is discussed.
- Published
- 2003
- Full Text
- View/download PDF
490. The immunological synapse.
- Author
-
Klemmensen T, Pedersen LO, and Geisler C
- Subjects
- Cell Adhesion, Cell Movement, Models, Immunological, Antigen-Presenting Cells immunology, Cell Communication physiology, Immune System physiology, T-Lymphocytes immunology
- Abstract
The induction of a proper adaptive immune response is dependent on the correct transfer of information between antigen-presenting cells (APCs) and antigen-specific T cells. Defects in information transfer may result in the development of diseases, e.g. immunodeficiencies and autoimmunity. A distinct 3-dimensional supramolecular structure at the T cell/APC interface has been suggested to be involved in the information transfer. Due to its functional analogy to the neuronal synapse, the structure has been termed the "immunological synapse" (IS). Here, we review molecular aspects concerning IS formation, appearance, and cessation. In addition, proposed functions of the IS are discussed. The process of IS formation occurs in a sequential manner, initially causing a remarkable large-scale redistribution of a number of integral membrane and cytosolic proteins. At the T cell/APC interface the structure comprises in its nascent stage a non-random pattern of protein distribution. The protein pattern is regulated during development of the mature IS and is finally organized into concentric rings of co-receptors and adhesive molecules surrounding the T cell antigen receptor (TCR). The relocations of proteins are influenced by passive as well as active mechanisms. Considering the IS as a device enabling cell-cell communication, clarification of its exact function is of huge general as well as therapeutic interest.
- Published
- 2003
491. The CD3 gamma leucine-based receptor-sorting motif is required for efficient ligand-mediated TCR down-regulation.
- Author
-
von Essen M, Menné C, Nielsen BL, Lauritsen JP, Dietrich J, Andersen PS, Karjalainen K, Ødum N, and Geisler C
- Subjects
- Amino Acid Motifs, Amino Acid Sequence, Animals, CD3 Complex genetics, Cell Line, Cells, Cultured, Gene Deletion, Humans, Jurkat Cells, Kinetics, Ligands, Mice, Molecular Sequence Data, Protein Kinase C physiology, Sequence Homology, CD3 Complex chemistry, Down-Regulation, Leucine chemistry, Receptor-CD3 Complex, Antigen, T-Cell metabolism, T-Lymphocytes immunology
- Abstract
TCR down-regulation plays an important role in modulating T cell responses both during T cell development and in mature T cells. At least two distinct pathways exist for down-regulation of the TCR. One pathway is activated following TCR ligation and is dependent on tyrosine phosphorylation. The other pathway is dependent on protein kinase C (PKC)-mediated activation of the CD3 gamma di-leucine-based receptor-sorting motif. Previous studies have failed to demonstrate a connection between ligand- and PKC-induced TCR down-regulation. Thus, although an apparent paradox, the dogma has been that ligand- and PKC-induced TCR down-regulations are not interrelated. By analyses of a newly developed CD3 gamma-negative T cell variant, freshly isolated and PHA-activated PBMC, and a mouse T cell line, we challenged this dogma and demonstrate in this work that PKC activation and the CD3 gamma di-leucine-based motif are indeed required for efficient ligand-induced TCR down-regulation.
- Published
- 2002
- Full Text
- View/download PDF
492. Spontaneous interleukin-5 production in cutaneous T-cell lymphoma lines is mediated by constitutively activated Stat3.
- Author
-
Nielsen M, Nissen MH, Gerwien J, Zocca MB, Rasmussen HM, Nakajima K, Röpke C, Geisler C, Kaltoft K, and Ødum N
- Subjects
- Cytokines analysis, Cytokines biosynthesis, DNA-Binding Proteins genetics, DNA-Binding Proteins metabolism, Humans, Interleukin-13 analysis, Interleukin-5 analysis, Interleukin-6 analysis, Lymphoma, T-Cell, Cutaneous immunology, Lymphoma, T-Cell, Cutaneous pathology, STAT3 Transcription Factor, T-Lymphocytes immunology, T-Lymphocytes metabolism, T-Lymphocytes pathology, Trans-Activators genetics, Trans-Activators metabolism, Transfection, Tumor Cells, Cultured, DNA-Binding Proteins pharmacology, Interleukin-5 biosynthesis, Lymphoma, T-Cell, Cutaneous metabolism, Trans-Activators pharmacology
- Abstract
Mycosis fungoides is a low-grade cutaneous T-cell lymphoma (CTCL) of unknown etiology. In advanced stages of CTCL, a shift in cytokine profile from T(H)1 to T(H)2 is observed, which coincides with eosinophilia, high levels of immunoglobulin E, and increased susceptibility to bacterial infections. It is, however, unknown why T(H)2 cytokines predominate in advanced CTCL, and the cellular source of these cytokines also remains to be identified. In several leukemias and lymphomas, constitutively activated signal transducer and activator of transcription (Stat) signaling pathways have been detected. In a previous study, constitutive activation of Stat3 was found in tumor cells isolated from affected skin and blood from CTCL patients. Here, it is shown that CTCL tumor cell lines, but not nonmalignant cell lines, spontaneously produce interleukin-5 (IL-5), IL-6, and IL-13. Transfection of tumor cells with dominant-negative Stat3 almost completely blocks IL-5 production and strongly inhibits IL-13 production, whereas IL-6 production is unaffected. Thus, the data show that malignant CTCL cells themselves might contribute to the change in cytokine pattern accompanying progression of CTCL. In conclusion, constitutively activated Stat3 is found to mediate a spontaneous IL-5 production and regulate IL-13 production in CTCL cell lines, pointing toward a new role of Stat3 in malignant transformation.
- Published
- 2002
- Full Text
- View/download PDF
Catalog
Discovery Service for Jio Institute Digital Library
For full access to our library's resources, please sign in.