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Article ; Online: CD28-Kostimulation und Checkpointblockade in T-Zellen.

Beyersdorf, N / Kerkau, T

2020 Volume 61, Issue 7, Page(s) 652–659

Abstract: Background: The induction of protective T cell responses requires two signals: Signal 1 is generated by activation of the T cell receptor (TCR) and signal 2 results from ligation of the CD28 molecule. Costimulation of the TCR and CD28 is necessary, as ... ...

Title translation	CD28 costimulation and checkpoint inhibition in T cells.
Abstract	Background: The induction of protective T cell responses requires two signals: Signal 1 is generated by activation of the T cell receptor (TCR) and signal 2 results from ligation of the CD28 molecule. Costimulation of the TCR and CD28 is necessary, as the TCR is very good at discriminating between endogenous and foreign structures (antigens), but not all foreign antigens (such as food antigens) are dangerous to the body. A strong CD28 signal, thus, indicates to the T cell that there is indeed a threat and that an immune response is urgently required. However, to avoid autoimmunity and excessive immune responses, further regulatory circuits, provided by immune checkpoints, are necessary. Objectives: To provide an introduction to immunoregulation mediated by checkpoint molecules. Materials and methods: Review of basic science papers and reports on clinical studies. Results: The most prominent and best characterized checkpoint molecules, cytotoxic T lymphocyte-associated protein‑4 (CTLA-4) and programmed cell death‑1 (PD-1), both physiologically dampen CD28-mediated costimulation. Pathologically, malignancies exploit the immunoregulatory function of checkpoint molecules by, for example, expressing ligands for PD‑1 on the cell surface, thus, avoiding being attacked by T cells. Our understanding of these negative feedback regulations has led to the development of checkpoint inhibitors, which have already become part of routine clinical care of cancer patients. Conclusions: Due to the clinical success of checkpoint inhibitors, the concept of cancer immunotherapy has received a massive boost and hopes are high that many more clinical advancements in cancer therapy can be achieved with novel forms of immunotherapy.
MeSH term(s)	Antigens, CD ; CD28 Antigens/physiology ; CTLA-4 Antigen ; Humans ; Immunotherapy ; T-Lymphocytes/immunology
Chemical Substances	Antigens, CD ; CD28 Antigens ; CTLA-4 Antigen
Language	German
Publishing date	2020-05-28
Publishing country	Germany
Document type	Journal Article ; Review
ZDB-ID	2913-0
ISSN	1432-1289 ; 0020-9554
ISSN (online)	1432-1289
ISSN	0020-9554
DOI	10.1007/s00108-020-00813-0
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Article ; Online: Insights into B-cell ontogeny inferred from human immunology.

Dirks, Johannes / Viemann, Dorothee / Beyersdorf, Niklas / Härtel, Christoph / Morbach, Henner

European journal of immunology

2023 Volume 53, Issue 6, Page(s) e2250116

Abstract: Due to ontogenetic changes in B-cell developmental lineages, the mature B-cell compartment constitutes by functionally different B-cell subsets that emerged from prenatal, early postnatal or adult precursors. While negative selection processes operate ... ...

Abstract	Due to ontogenetic changes in B-cell developmental lineages, the mature B-cell compartment constitutes by functionally different B-cell subsets that emerged from prenatal, early postnatal or adult precursors. While negative selection processes operate primarily within the framework of B-cell tolerance checkpoints during B-cell development, further differentiation into distinct B-cell subsets is additionally induced by positive selection. In addition to endogenous antigens, contact with microbial antigens is also involved in this selection process, with intestinal commensals having a significant influence on the development of a large layer within the B-cell compartment. The decisive threshold that triggers negative selection seems to be relaxed during fetal B-cell development, thereby allowing recruitment of polyreactive and also autoreactive B-cell clones into the mature naïve B-cell compartment. Almost all of the concepts on B-cell ontogeny are based on observations in laboratory mice that not only differ from humans in their developmental timeline but also in their composition of commensal microorganisms or rather a lack of exposure to these. In this review, we summarize conceptual findings on B-cell ontogeny and particularly describe key insights into the developing human B-cell compartment and immunoglobulin repertoire formation.
MeSH term(s)	Mice ; Animals ; Adult ; Humans ; B-Lymphocytes ; B-Lymphocyte Subsets ; Antigens ; Immune Tolerance ; Cell Differentiation
Chemical Substances	Antigens
Language	English
Publishing date	2023-04-05
Publishing country	Germany
Document type	Journal Article ; Review ; Research Support, Non-U.S. Gov't
ZDB-ID	120108-6
ISSN	1521-4141 ; 0014-2980
ISSN (online)	1521-4141
ISSN	0014-2980
DOI	10.1002/eji.202250116
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Article ; Online: Systemic CD4 cytotoxic T cells improve protection against PRRSV-1 transplacental infection.

Li, Yanli / Díaz, Ivan / Martín-Valls, Gerard / Beyersdorf, Niklas / Mateu, Enric

Frontiers in immunology

2023 Volume 13, Page(s) 1020227

Abstract: ... n=8) or healthy (n=10) piglets. After that, functions of CTL, NKT, and NK cells in the two groups ...

Abstract	Background: Porcine reproductive and respiratory syndrome virus Methods: The present study investigated the role of cytotoxic lymphocytes, including cytotoxic T cells (CTL), NKT, and NK cells, from blood in preventing PRRSV-1 transplacental infection in vaccinated primiparous sows (two doses vaccinated). Sows from a PRRSV-1 unstable farm were bled just before the last month of gestation (critical period for transplacental infection), then followed to determine whether sows delivered PRRSV-1-infected (n=8) or healthy (n=10) piglets. After that, functions of CTL, NKT, and NK cells in the two groups of sows were compared. Results: No difference was found through cell surface staining. But upon Conclusion: Our data strongly suggest that CTL responses correlate with protection against PRRSV-1 transplacental infection, being executed by CD4 T cells (IFN-γ related) and/or CD4/CD8α DN T cells (TNF-α related).
MeSH term(s)	Swine ; Animals ; Female ; Porcine respiratory and reproductive syndrome virus ; Porcine Reproductive and Respiratory Syndrome/prevention & control ; T-Lymphocytes, Cytotoxic ; Tumor Necrosis Factor-alpha ; Antibodies, Viral ; Vaccines, Attenuated
Chemical Substances	Tumor Necrosis Factor-alpha ; Antibodies, Viral ; Vaccines, Attenuated
Language	English
Publishing date	2023-01-17
Publishing country	Switzerland
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2606827-8
ISSN	1664-3224 ; 1664-3224
ISSN (online)	1664-3224
ISSN	1664-3224
DOI	10.3389/fimmu.2022.1020227
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Article ; Online: Analyzing trogocytosis of T lymphocytes by flow cytometry and confocal microscopy.

Zink, Alicia / Zenke, Simon / Wiese, Teresa / Beyersdorf, Niklas / Lämmermann, Tim / Rohr, Jan C

STAR protocols

2023 Volume 4, Issue 1, Page(s) 102013

Abstract: Here, we present a protocol to examine the mechanisms underlying the intercellular transfer of transmembrane molecules, termed trogocytosis, and the fate of transferred molecules. We describe the steps needed from T lymphocyte isolation, via co-culture ... ...

Abstract	Here, we present a protocol to examine the mechanisms underlying the intercellular transfer of transmembrane molecules, termed trogocytosis, and the fate of transferred molecules. We describe the steps needed from T lymphocyte isolation, via co-culture with cells expressing the ligand of interest, to cell harvest and subsequent staining for flow cytometry and confocal microscopy. Furthermore, we showcase critical parameters and pitfalls, which allow easy adaptation of the protocol to investigate trogocytosis of various cell surface receptors in different cell types. For complete details on the use and execution of this protocol, please refer to Zink and Rohr.
MeSH term(s)	Flow Cytometry ; T-Lymphocytes ; Trogocytosis ; Microscopy, Confocal ; Coculture Techniques
Language	English
Publishing date	2023-01-11
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2666-1667
ISSN (online)	2666-1667
DOI	10.1016/j.xpro.2022.102013
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Article ; Online: Aspergillus fumigatus-Specific T Cells in Patients with Chronic Rhinosinusitis.

Ickrath, Pascal / Sprügel, Lisa / Beyersdorf, Niklas / Haug, Lukas / Scherzad, Agmal / Hagen, Rudolf / Hackenberg, Stephan

International archives of allergy and immunology

2023 Volume 184, Issue 5, Page(s) 502–512

Abstract: Introduction: Aspergillus fumigatus belongs to the saprophytic fungi, and its spores form a significant part of the daily load of fungal spores inhaled as particles in aerosols. A. fumigatus is a possible T-cell activator. Its contribution to the ... ...

Abstract	Introduction: Aspergillus fumigatus belongs to the saprophytic fungi, and its spores form a significant part of the daily load of fungal spores inhaled as particles in aerosols. A. fumigatus is a possible T-cell activator. Its contribution to the pathogenesis of chronic rhinosinusitis (CRS) is controversially discussed. The aim of this study was to detect and characterize A. fumigatus-specific CD4+ and CD8+ T cells in patients with CRS with (CRSwNP) and without (CRSsNP) nasal polyps. Methods: Tissue and blood samples were collected from patients who underwent paranasal sinus surgery due to CRSwNP or CRSsNP. Afterward, purified CD4+ and CD8+ cells were cultured together with antigen-presenting cells. A peptide mix derived from A. fumigatus antigen was added to the cultures. After 6 days, multicolor flow cytometry was performed, and proliferation was measured using the marker Ki-67. Cytokine secretion was quantified from the supernatant of the cell culture. Results: Significant differences in the proliferation of nasal CD4+ T cells to A. fumigatus antigen were observed for cells from patients with CRSwNP in comparison to CRSsNP, while no differences were found between nasal and peripheral blood T cells. The activation of tissue-derived CD4+ T cells was associated with significantly higher concentrations of IL-4, IL-5, and IL-17a in the cell culture from patients with CRSwNP in comparison to CRSsNP and/or healthy controls. Conclusion: Our findings indicate that patients with CRSwNP harbor a higher proportion of A. fumigatus-reactive CD4+ T cells in the nasal mucosa than patients with CRSsNP. A. fumigatus-reactive CD4+ T cells of CRSwNP patients secreted TH2 cytokines and IL-17. Our findings suggest a role for A. fumigatus in the pathogenesis of CRSwNP and provide a rationale for targeted therapies.
MeSH term(s)	Humans ; Aspergillus fumigatus ; Rhinitis ; Sinusitis ; Nasal Mucosa ; CD4-Positive T-Lymphocytes ; Chronic Disease ; Nasal Polyps
Language	English
Publishing date	2023-01-18
Publishing country	Switzerland
Document type	Journal Article
ZDB-ID	1108932-5
ISSN	1423-0097 ; 1018-2438
ISSN (online)	1423-0097
ISSN	1018-2438
DOI	10.1159/000528394
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Article: Branched endovascular iliac artery repair using the Zenith

Benk, Julia / Kreibich, Maximilian / Berger, Tim / Kondov, Stoyan / Beyersdorf, Friedhelm / Czerny, Martin / Rylski, Bartosz

Cardiovascular diagnosis and therapy

2023 Volume 13, Issue 4, Page(s) 700–709

Abstract: ... common indication for reinterventions (n=14, 61%). The internal iliac artery's diameter [subdistribution ...

Abstract	Background: The aim of this retrospective cohort study was to analyze the outcomes and the need for reinterventions following branched iliac artery repair using the Zenith Methods: Patient characteristics and follow-up data on 63 patients following branched iliac artery repair using the ZBIS device were evaluated and compared between patients with and without iliac reinterventions. A competing risk regression model was analyzed to identify independent predictors of reinterventions, and to predict the reintervention risk. Results: ZBIS implantation's technical success rate was 100%, and we observed no in-hospital mortality. Internal iliac artery patency was 93% during a median [first quartile, third quartile] follow-up of 19 [5, 39] months. Thirty-two iliac reinterventions were performed in 23 patients (37%) after a mean time of 3.0 months (IQR: 0.4-6.8) (time to first reintervention). Endoleaks type I and II were the most common indication for reinterventions (n=14, 61%). The internal iliac artery's diameter [subdistribution hazard ratio (sHR): 1.046; P=0.0015] and a prior abdominal aortic intervention (sHR: 0.3331; P=0.0370) were identified as significant variables in the competing risk regression model for a reintervention. The risk for reintervention was 33% (95% CI: 20-46%), and 46% (95% CI: 28-63%) after 12 and 36 months, respectively. Conclusions: Endovascular repair of degenerative iliac artery aneurysms with Zenith Branch Iliac Bifurcation device is a feasible and safe option. Perioperative morbidity and mortality are low with good graft patency rates. The risk for secondary iliac artery interventions is considerable and highlights the need for patients with iliac disease to undergo continuous follow-up in a dedicated vascular center.
Language	English
Publishing date	2023-07-28
Publishing country	China
Document type	Journal Article
ZDB-ID	2685043-6
ISSN	2223-3660 ; 2223-3652
ISSN (online)	2223-3660
ISSN	2223-3652
DOI	10.21037/cdt-22-564
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Article: A lipopeptidomimetic of transcriptional activation domains selectively disrupts Med25 PPIs.

Pattelli, Olivia N / Valdivia, Estefanía Martínez / Beyersdorf, Matthew S / Regan, Clint S / Rivas, Mónica / Merajver, Sofia D / Cierpicki, Tomasz / Mapp, Anna K

bioRxiv : the preprint server for biology

2023

Abstract: ... that incorporation of a medium-chain, branched fatty acid to the N-terminus of one such heptameric lipopeptidomimetic ...

Abstract	Short amphipathic peptides are capable of binding to transcriptional coactivators, often targeting the same binding surfaces as native transcriptional activation domains. However, they do so with modest affinity and generally poor selectivity, limiting their utility as synthetic modulators. Here we show that incorporation of a medium-chain, branched fatty acid to the N-terminus of one such heptameric lipopeptidomimetic (34913-8) increases the affinity for the coactivator Med25 >10-fold (
Language	English
Publishing date	2023-03-25
Publishing country	United States
Document type	Preprint
DOI	10.1101/2023.03.24.534168
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Article ; Online: CD4+ Foxp3+ regulatory T cell-mediated immunomodulation by anti-depressants inhibiting acid sphingomyelinase.

Schneider-Schaulies, Jürgen / Beyersdorf, Niklas

Biological chemistry

2018 Volume 399, Issue 10, Page(s) 1175–1182

Abstract: Acid sphingomyelinase (ASM) is the rate-limiting enzyme cleaving sphingomyelin into ceramide and phosphorylcholin. CD4+ Foxp3+ regulatory T (Treg) cells depend on CD28 signaling for their survival and function, a receptor that activates the ASM. Both, ... ...

Abstract	Acid sphingomyelinase (ASM) is the rate-limiting enzyme cleaving sphingomyelin into ceramide and phosphorylcholin. CD4+ Foxp3+ regulatory T (Treg) cells depend on CD28 signaling for their survival and function, a receptor that activates the ASM. Both, basal and CD28-induced ASM activities are higher in Treg cells than in conventional CD4+ T (Tconv) cells. In ASM-deficient (Smpd1-/-) as compared to wt mice, membranes of T cells contain 7-10-fold more sphingomyelin and two- to three-fold more ceramide, and are in a state of higher order than membranes of T cells from wt mice, which may facilitate their activation. Indeed, the frequency of Treg cells among CD4+ T cells in ASM-deficient mice and their suppressive activity in vitro are increased. Moreover, in vitro stimulation of ASM-deficient T cells in the presence of TGF-β and IL-2 leads to higher numbers of induced Treg cells. Pharmacological inhibition of the ASM with a clinically used tricyclic antidepressant such as amitriptyline in mice or in tissue culture of murine or human T cells induces higher frequencies of Treg cells among CD4+ T cells within a few days. This fast alteration of the balance between T cell populations in vitro is due to the elevated cell death of Tconv cells and protection of the CD25high Treg cells by IL-2. Together, these findings suggest that ASM-inhibiting antidepressants, including a fraction of the serotonin re-uptake inhibitors (SSRIs), are moderately immunosuppressive and should be considered for the therapy of inflammatory and autoimmune disorders.
MeSH term(s)	Amitriptyline/pharmacology ; Animals ; Antidepressive Agents/pharmacology ; Autoimmune Diseases/therapy ; Forkhead Transcription Factors/metabolism ; Humans ; Immunomodulation/drug effects ; Inflammation/therapy ; Mice ; Sphingomyelin Phosphodiesterase/antagonists & inhibitors ; Sphingomyelin Phosphodiesterase/deficiency ; Sphingomyelin Phosphodiesterase/metabolism ; T-Lymphocytes, Regulatory/immunology ; T-Lymphocytes, Regulatory/metabolism
Chemical Substances	Antidepressive Agents ; FOXP3 protein, human ; Forkhead Transcription Factors ; Foxp3 protein, mouse ; Amitriptyline (1806D8D52K) ; Sphingomyelin Phosphodiesterase (EC 3.1.4.12)
Language	English
Publishing date	2018-04-27
Publishing country	Germany
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1334659-3
ISSN	1437-4315 ; 1431-6730 ; 1432-0355
ISSN (online)	1437-4315
ISSN	1431-6730 ; 1432-0355
DOI	10.1515/hsz-2018-0159
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Article ; Online: A Lipopeptidomimetic of Transcriptional Activation Domains Selectively Disrupts the Coactivator Med25 Protein-Protein Interactions.

Pattelli, Olivia N / Valdivia, Estefanía Martínez / Beyersdorf, Matthew S / Regan, Clint S / Rivas, Mónica / Hebert, Katherine A / Merajver, Sofia D / Cierpicki, Tomasz / Mapp, Anna K

Angewandte Chemie (International ed. in English)

2024 , Page(s) e202400781

Abstract: ... that incorporation of a medium-chain, branched fatty acid to the N-terminus of one such heptameric lipopeptidomimetic ...

Abstract	Short amphipathic peptides are capable of binding to transcriptional coactivators, often targeting the same binding surfaces as native transcriptional activation domains. However, they do so with modest affinity and generally poor selectivity, limiting their utility as synthetic modulators. Here we show that incorporation of a medium-chain, branched fatty acid to the N-terminus of one such heptameric lipopeptidomimetic (LPPM-8) increases the affinity for the coactivator Med25 >20-fold (Ki >100 μM to 4 μM), rendering it an effective inhibitor of Med25 protein-protein interactions (PPIs). The lipid structure, the peptide sequence, and the C-terminal functionalization of the lipopeptidomimetic each influence the structural propensity of LPPM-8 and its effectiveness as an inhibitor. LPPM-8 engages Med25 through interaction with the H2 face of its activator interaction domain and in doing so stabilizes full-length protein in the cellular proteome. Further, genes regulated by Med25-activator PPIs are inhibited in a cell model of triple-negative breast cancer. Thus, LPPM-8 is a useful tool for studying Med25 and mediator complex biology and the results indicate that lipopeptidomimetics may be a robust source of inhibitors for activator-coactivator complexes.
Language	English
Publishing date	2024-03-25
Publishing country	Germany
Document type	Journal Article
ZDB-ID	2011836-3
ISSN	1521-3773 ; 1433-7851
ISSN (online)	1521-3773
ISSN	1433-7851
DOI	10.1002/anie.202400781
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Article ; Online: Efficacy of lysostaphin-coated titanium plates on implant-associated MRSA osteitis in minipigs.

Jaekel, Carina / Windolf, Ceylan D / Bieler, Dan / Oezel, Lisa / Seiler, Lars F / Lakomek, Felix N / Beyersdorf, Christoph / Mertens, Jann / Steuwe, Andrea / Windolf, Joachim / Grassmann, Jan P

European journal of trauma and emergency surgery : official publication of the European Trauma Society

2024

Abstract: Purpose: The growing incidence of implant-associated infections (IAIs) caused by biofilm-forming Staphylococcus aureus in combination with an increasing resistance to antibiotics requires new therapeutic strategies. Lysostaphin has been shown to ... ...

Abstract	Purpose: The growing incidence of implant-associated infections (IAIs) caused by biofilm-forming Staphylococcus aureus in combination with an increasing resistance to antibiotics requires new therapeutic strategies. Lysostaphin has been shown to eliminate this biofilm. Own studies confirm the effectiveness in a murine model. The current study characterizes the effects of lysostaphin-coated plates in an IAI minipig model. Methods: The femur of 30 minipigs was stabilized with a five-hole plate, a bone defect was created, and in 20 cases methicillin-resistant Staphylococcus aureus was applied. Ten animals served as control group. After 14 days, local debridement, lavage, and plate exchange (seven-hole plate) were performed. Ten of the infected minipigs received an uncoated plate and 10 a lysostaphin-coated plate. On day 84, the minipigs were again lavaged, followed by euthanasia. Bacterial load was quantified by colony-forming units (CFU). Immunological response was determined by neutrophils, as well as interleukins. Fracture healing was assessed radiologically. Results: CFU showed significant difference between infected minipigs with an uncoated plate and minipigs with a lysostaphin-coated plate (p = 0.0411). The infection-related excessive callus formation and calcification was significantly greater in the infected animals with an uncoated plate than in animals with a lysostaphin-coated plate (p = 0.0164/p = 0.0033). The analysis of polymorphonuclear neutrophils and interleukins did not reveal any pioneering findings. Conclusion: This study confirms the minipig model for examining IAI. Furthermore, coating of plates using lysostaphin could be a promising tool in the therapeutic strategies of IAI. Future studies should focus on coating technology of implants and on translation into a clinical model.
Language	English
Publishing date	2024-01-24
Publishing country	Germany
Document type	Journal Article
ZDB-ID	2275480-5
ISSN	1863-9941 ; 1863-9933
ISSN (online)	1863-9941
ISSN	1863-9933
DOI	10.1007/s00068-024-02448-4
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