Ester B. M. Remmerswaal

Amsterdam University Medical Centers

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René A. W. van Lier

University Medical Center Utrecht

Ineke J. M. ten Berge

Amsterdam University Medical Centers

Fréderike J. Bemelman

University of Amsterdam

Debbie van Baarle

University Medical Center Groningen

Ester M. M. van Leeuwen

University of Amsterdam

Luuk B. Hilbrands

Radboud University Nijmegen

Eric Eldering

University of Amsterdam

Marlies E. J. Reinders

Leiden University Medical Center

Dimitri A. Diavatopoulos

Radboud University Medical Center

Carla C. Baan

Erasmus MC

Cooperative Institutions

University of Amsterdam

241

Academic Medical Center

211

Amsterdam University Medical Centers

197

Leiden University Medical Center

Sanquin

Charité - Universitätsmedizin Berlin

Erasmus MC

Institute of Infection and Immunity

European Foundation for the Study of Chronic Liver Failure

Vrije Universiteit Amsterdam

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Tissue‐resident mucosal‐associated invariant T (MAIT) cells in the human kidney represent a functionally distinct subset

European Journal of Immunology (2020)

Matty L. Terpstra Ester B. M. Remmerswaal Nelly D. van der Bom‐Baylon Marjan J. Sinnige Jesper Kers

Mucosal-associated invariant T (MAIT) cells are innate-like T-cells that recognize bacterial riboflavin metabolites. They are present in human blood but are abundant at barrier sites, including the liver, lungs, and kidneys, where they possess a CD69+ /CD103+/- tissue-resident phenotype. In renal tissue, MAIT cells likely defend against the ascending uropathogens responsible for urinary tract infections (UTIs), which are common, especially among renal transplant recipients (RTRs). Nevertheless, the functional role for MAIT cells in renal tissue and the influence of renal transplantation on MAIT cells remains unclear. Using multiparameter flow cytometry and the MR1-tetramer, we characterized MAIT cell phenotype and function in healthy renal tissue (n = 6), renal transplants explanted after allograft failure (n = 14) and in blood from healthy controls (n = 20) and RTRs before and 1-year after transplantation (n = 21). MAIT cells in renal tissue constitute a distinct CD69+ CD103+/- population that displays typical phenotypic features of tissue-resident T-cells and is skewed toward IL-2, GM-CSF, and IL-17A production upon stimulation. The circulating MAIT cell population was not decreased in number in RTRs pre- or post-transplantation. Tissue-resident MAIT cells in the kidney represent a functionally distinct population. This shows how MAIT cells in the kidney may be involved in the protection against microorganisms.

10.1002/eji.202048644

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<p>Butyrate production in patients with end-stage renal disease</p>

International Journal of Nephrology and Renovascular Disease (2019)

Matty L. Terpstra Marjan J. Sinnige Floor Hugenholtz Hessel Peters‐Sengers Ester B. M. Remmerswaal

Background: Chronic kidney disease (CKD) is associated with a decreased intestinal barrier function, causing bacterial translocation over the intestinal wall and triggering a systemic inflammatory response. Butyrate, a short-chain fatty acid produced by certain bacterial strains, is considered instrumental to keep the intestinal barrier intact. There are indications that a decreased amount of these specific bacterial species is part of the cause of the decreased intestinal barrier function in CKD. The aim of this study is (i) to determine if Dutch patients with end-stage renal disease (ESRD) have a decreased amount of butyrate-producing species and butyrate-producing capacity and (ii) whether this correlates with systemic inflammation. Methods: We used qPCR to evaluate the most abundant butyrate-producing species F. prauznitzii, E. rectale and Roseburia spp. and the BCoAT gene, which reflects the butyrogenic capacity of the intestinal microbiota. Fecal samples were collected from healthy kidney donors (n=15), preemptive renal transplant recipients (n=4) and dialysis patients (n=31). Markers of inflammation (CRP and IL-6) and intestinal permeability (D-lactate) were measured in plasma. Results: Patients with ESRD did not have a significantly decreased amount F. prauznitzii, E. rectale and Roseburia spp. or the BCoAT gene. Neither was there a significant correlation with CRP, IL-6 or D-lactate. On the individual level, there were some patients with decreased BCoAT levels and increased levels of CRP, IL-6 and D-lactate. Conclusions: Patients with ESRD do not have a decreased amount of the most abundant butyrate-producing species nor a decreased butyrate-producing capacity.

10.2147/ijnrd.s200297

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A Single 17D Yellow Fever Vaccination Provides Lifelong Immunity; Characterization of Yellow-Fever-Specific Neutralizing Antibody and T-Cell Responses after Vaccination

PLoS ONE (2016)

Rosanne W. Wieten Emile F.F. Jonker Ester M. M. van Leeuwen Ester B. M. Remmerswaal Ineke J. M. ten Berge

Introduction Prompted by recent amendments of Yellow Fever (YF) vaccination guidelines from boost to single vaccination strategy and the paucity of clinical data to support this adjustment, we used the profile of the YF-specific CD8+ T-cell subset profiles after primary vaccination and neutralizing antibodies as a proxy for potentially longer lasting immunity. Methods and Findings PBMCs and serum were collected in six individuals on days 0, 3, 5, 12, 28 and 180, and in 99 individuals >10 years after YF-vaccination. Phenotypic characteristics of YF- tetramer+ CD8+ T-cells were determined using class I tetramers. Antibody responses were measured using a standardized plaque reduction neutralization test (PRNT). Also, characteristics of YF-tetramer positive CD8+ T-cells were compared between individuals who had received a primary- and a booster vaccination. YF-tetramer+ CD8+ T-cells were detectable on day 12 (median tetramer+ cells as percentage of CD8+ T-cells 0.2%, range 0.07–3.1%). On day 180, these cells were still present (median 0.06%, range 0.02–0.78%). The phenotype of YF-tetramer positive CD8+ T-cells shifted from acute phase effector cells on day 12, to late differentiated or effector memory phenotype (CD45RA-/+CD27-) on day 28. Two subsets of YF-tetramer positive T-cells (CD45RA+CD27- and CD45RA+CD27+) persisted until day 180. Within all phenotypic subsets, the T-bet: Eomes ratio tended to be high on day 28 after vaccination and shifted towards predominant Eomes expression on day 180 (median 6.0 (day 28) vs. 2.2 (day 180) p = 0.0625), suggestive of imprinting compatible with long-lived memory properties. YF-tetramer positive CD8+ T-cells were detectable up to 18 years post vaccination, YF-specific antibodies were detectable up to 40 years after single vaccination. Booster vaccination did not increase titers of YF-specific antibodies (mean 12.5 vs. 13.1, p = 0.583), nor induce frequencies or alter phenotypes of YF-tetramer+ CD8+ T-cells. Conclusion The presence of a functionally competent YF-specific memory T-cell pool 18 years and sufficient titers of neutralizing antibodies 35–40 years after first vaccination suggest that single vaccination may be sufficient to provide long-term immunity.

Memory T cell

10.1371/journal.pone.0149871

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POS0003 HUMAN LYMPH NODE STROMAL CELLS MAINTAIN FOXP3+ REGULATORY T CELLS IN A HLA-DR DEPENDENT MANNER

Annals of the Rheumatic Diseases (2023)

Cristoforo Grasso A. M. O’byrne Johanna F. Semmelink Ester B. M. Remmerswaal Janne W. Bolt

Background

Animal studies have shown that lymph node stromal cells (LNSCs) are key players in peripheral tolerance through their capacity to present self-antigens in MHC class II to CD4+ T cells thereby controlling auto-reactivity and humoral response. Thus, it has been suggested that dysfunctional LNSCs may play a role in the breaking of tolerance observed in autoimmune diseases like rheumatoid arthritis (RA), where there is a genetic association with the HLA-DR locus.

Objectives

We hypothesise that human LNSCs from healthy individuals without autoimmunity can express HLA-DR and maintain FOXP3+ regulatory T cells, a process which may be disturbed in LNSCs from RA patients.

Methods

Lymph node needle biopsies were collected from healthy volunteers, autoantibody positive RA-risk individuals and RA patients. In addition, lymph node stromal cells (fibroblasts) and paired peripheral blood mononuclear cells were obtained from non-RA controls. A combination of imaging techniques including spectral analyser, ImageStream, confocal and electron microscopy was used to determine the expression of HLA-DR directly ex vivo and on in vitro cultured LNSCs. To investigate the ability of these LNSCs to maintain regulatory T cells we employed an in vitro system where LNSCs were co-cultured with autologous CD4+ T cells for 72 hours. Subsequently flow cytometry analysis was used to determine the presence of FOXP3+ regulatory T cells.

Results

The presence of lymphocytes induced HLA-DR expression on cultured LNSCs from non-RA controls. The presence of LNSCs within this autologous co-culture model is crucial for maintaining CD25+ CD127- FOXP3+ regulatory T cells. To investigate possible mechanisms for this maintenance we used blocking antibodies for both HLA-DR and interleukin 2 (IL-2) in our system and showed that the maintenance of FOXP3+ regulatory T cells required both HLA-DR and IL-2. In the context of autoimmunity we were able to show that lymph node biopsies from RA patients directly analysed ex vivo have a significant reduction in the frequency of HLA-DR+ LNSCs compared to control individuals and those at risk of developing the disease.

Conclusion

Overall, these results indicate an important role for HLA-DR expressing LNSCs in maintaining tolerance within the lymph node, a process that may be dysfunctional in the context of autoimmunity where tolerance is broken.

Acknowledgements

We thank our study subjects for participating in the study, the AMC radiology department for lymph node tissue sampling and the rheumatology lab for sample processing. The research leading to these results was funded by an AMC fellowship (to L.G.M.v.B.), the Dutch Arthritis Foundation LLP-30, a ZonMw TOP project 91217014 and the Dutch Organization for Health Research and Development (ZonMw) VIDI n° 91718371 (to L.G.M.v.B).

Disclosure of Interests

None Declared.

Peripheral tolerance

Ex vivo

10.1136/annrheumdis-2023-eular.3749

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NKp44/HLA-DP-dependent regulation of CD8 effector T cells by NK cells

Cell Reports (2024)

Benedetta Padoan Christian Casar Jenny Krause Christoph Schultheiß Martin E. Baumdick

Although natural killer (NK) cells are recognized for their modulation of immune responses, the mechanisms by which human NK cells mediate immune regulation are unclear. Here, we report that expression of human leukocyte antigen (HLA)-DP, a ligand for the activating NK cell receptor NKp44, is significantly upregulated on CD8

10.1016/j.celrep.2024.114089

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hCMV-Specific CD8+ T Cells in Lymph Nodes from Renal Transplant Recipients Contain ‘True’ Memory Cells

Transplantation (2012)

Ester B. M. Remmerswaal P. M. Klarenbeek Marieke E. Doorenspleet Barbera D. C. van Schaik K. A.M.I. van Donselaar

We have recently shown that lymph nodes (LN) contain hCMV-specific CD8+ T cells that resemble central memory cells, a phenotype that is not found in peripheral blood (PB). We have also shown that the LN hCMV-pp65-specific CD8+ T cell pool contained clones not found in PB. It is not known what the contribution of these LN hCMV-specific CD8+ T cells is to the PB pool upon viral recall. We therefore studied the contribution of these clones to the PB pool during CMV reactivation. Two patients experiencing a hCMV reactivation after kidney transplantation were studied. hCMV-pp65-specific CD8+ T cells of pre transplantation LN and paired PB, as well as PB obtained during reactivation and 1 year after transplantation were analyzed for clonal relationships by high-throughput-sequencing of the TCR-Vβ-CDR3 region. In the first patient the PB pool was restricted to one clone and the LN pool consisted of an identical clone and one extra unique clone. During two subsequent reactivations the CMV-specific pool remained restricted to the same dominant clone. Though the unique LN clone did not contribute to the PB pool, it could not be determined whether the vigorous expansion of the CMV-specific pool during both reactivations was caused by the LN derived clone or the PB derived clone, since both clones were identical. In the second patient both overlapping and unique clones were present in LNs and PB. The unique LN derived clones could be found to add substantially to the PB pool upon reactivation. In fact, at that time point the major clone was a LN derived one. However, also in this patient, not all unique LN clones added to the PB pool upon reactivation. In conclusion, LNs seem to harbor a unique pool of ‘true’ memory hCMV-pp65-specific CD8+ T cells that proliferate vigorously and contribute to the PB population upon antigenic recall.

10.1097/00007890-201211271-00851

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Autologous cytomegalovirus‐specific T cells as effector cells in immunotherapy of B cell chronic lymphocytic leukaemia

British Journal of Haematology (2004)

Arnon P. Kater Ester B. M. Remmerswaal Martijn A. Nolte Eric Eldering Marinus H. J. van Oers

Summary B‐cell chronic lymphocytic leukaemia (B‐CLL) cells express low levels of co‐stimulatory molecules and therefore fail to induce activation and differentiation of tumour‐specific T cells. We have shown that patients with B‐CLL have considerably expanded numbers of cytomegalovirus (CMV) reactive CD8 + T cells. This study demonstrated that B‐CLL cells loaded with CMV peptide not only promoted the ex vivo expansion of autologous, in vivo ‐generated virus‐specific T cells, but also constituted excellent target cells for these cytotoxic Tcells, even without ex vivo re‐stimulation. Directing virus‐specific T cells to B‐CLL may overcome the inadequate immunostimulatory capacity of these cells, which could be exploited for T‐cell mediated immunotherapy.

Ex vivo

10.1111/j.1365-2141.2004.05070.x

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Citations (14)

Contents

Journal of Hepatology (2016)

Richard Moreau Ramón Bataller Thomas Berg Jessica Zucman‐Rossi Rajiv Jalan

10.1016/s0168-8278(15)00824-7

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New advances in CMV and immunosenescence

Experimental Gerontology (2014)

Paolo Sansoni Rosanna Vescovini Francesco Fagnoni Arne N. Akbar Ramon Arens

Immunosenescence, defined as the age-associated dysregulation and dysfunction of the immune system, is characterized by impaired protective immunity and decreased efficacy of vaccines. An increasing number of immunological, clinical and epidemiological studies suggest that persistent Cytomegalovirus (CMV) infection is associated with accelerated aging of the immune system and with several age-related diseases. However, current evidence on whether and how human CMV (HCMV) infection is implicated in immunosenescence and in age-related diseases remains incomplete and many aspects of CMV involvement in immune aging remain controversial. The attendees of the 4th International Workshop on "CMV & Immunosenescence", held in Parma, Italy, 25-27th March, 2013, presented and discussed data related to these open questions, which are reported in this commentary.

Immunosenescence

Cytomegalovirus

Immune Dysfunction

10.1016/j.exger.2014.03.020

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Guidelines for the use of flow cytometry and cell sorting in immunological studies (second edition)

European Journal of Immunology (2019)

Andrea Cossarizza Hyun‐Dong Chang Andreas Radbruch Andreas Acs Dieter Adam

These guidelines are a consensus work of a considerable number of members of the immunology and flow cytometry community. They provide the theory and key practical aspects of flow cytometry enabling immunologists to avoid the common errors that often undermine immunological data. Notably, there are comprehensive sections of all major immune cell types with helpful Tables detailing phenotypes in murine and human cells. The latest flow cytometry techniques and applications are also described, featuring examples of the data that can be generated and, importantly, how the data can be analysed. Furthermore, there are sections detailing tips, tricks and pitfalls to avoid, all written and peer-reviewed by leading experts in the field, making this an essential research companion.

Mass cytometry

Cytometry

10.1002/eji.201970107

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Citations (866)