Publications by authors named "Reina E Mebius"

83 Publications

Tertiary Lymphoid Structures: Diversity in Their Development, Composition, and Role.

J Immunol 2021 Jan;206(2):273-281

Department of Molecular Cell Biology and Immunology, Amsterdam Infection and Immunity Institute, Amsterdam University Medical Center, Vrije Universiteit, 1081HZ Amsterdam, the Netherlands;

Lymph node stromal cells coordinate the adaptive immune response in secondary lymphoid organs, providing both a structural matrix and soluble factors that regulate survival and migration of immune cells, ultimately promoting Ag encounter. In several inflamed tissues, resident fibroblasts can acquire lymphoid-stroma properties and drive the formation of ectopic aggregates of immune cells, named tertiary lymphoid structures (TLSs). Mature TLSs are functional sites for the development of adaptive responses and, consequently, when present, can have an impact in both autoimmunity and cancer conditions. In this review, we go over recent findings concerning both lymph node stromal cells and TLSs function and formation and further describe what is currently known about their role in disease, particularly their potential in tolerance.
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http://dx.doi.org/10.4049/jimmunol.2000873DOI Listing
January 2021

Human Lymph Node Stromal Cells Have the Machinery to Regulate Peripheral Tolerance during Health and Rheumatoid Arthritis.

Int J Mol Sci 2020 Aug 9;21(16). Epub 2020 Aug 9.

Department of Rheumatology & Clinical Immunology and Department of Experimental Immunology, Amsterdam Infection & Immunity Institute, Amsterdam UMC, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.

Background: In rheumatoid arthritis (RA) the cause for loss of tolerance and anti-citrullinated protein antibody (ACPA) production remains unidentified. Mouse studies showed that lymph node stromal cells (LNSCs) maintain peripheral tolerance through presentation of peripheral tissue antigens (PTAs). We hypothesize that dysregulation of peripheral tolerance mechanisms in human LNSCs might underlie pathogenesis of RA.

Method: Lymph node (LN) needle biopsies were obtained from 24 RA patients, 23 individuals positive for RA-associated autoantibodies but without clinical disease (RA-risk individuals), and 14 seronegative healthy individuals. Ex vivo human LNs from non-RA individuals were used to directly analyze stromal cells. Molecules involved in antigen presentation and immune modulation were measured in LNSCs upon interferon γ (IFNγ) stimulation ( = 15).

Results: Citrullinated targets of ACPAs were detected in human LN tissue and in cultured LNSCs. Human LNSCs express several PTAs, transcription factors autoimmune regulator (AIRE) and deformed epidermal autoregulatory factor 1 (DEAF1), and molecules involved in citrullination, antigen presentation, and immunomodulation. Overall, no clear differences between donor groups were observed with exception of a slightly lower induction of human leukocyte antigen-DR (HLA-DR) and programmed cell death 1 ligand (PD-L1) molecules in LNSCs from RA patients.

Conclusion: Human LNSCs have the machinery to regulate peripheral tolerance making them an attractive target to exploit in tolerance induction and maintenance.
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http://dx.doi.org/10.3390/ijms21165713DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7460812PMC
August 2020

A molecular map of murine lymph node blood vascular endothelium at single cell resolution.

Nat Commun 2020 07 30;11(1):3798. Epub 2020 Jul 30.

Laboratory of Immunology and Vascular Biology, Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.

Blood vascular endothelial cells (BECs) control the immune response by regulating blood flow and immune cell recruitment in lymphoid tissues. However, the diversity of BEC and their origins during immune angiogenesis remain unclear. Here we profile transcriptomes of BEC from peripheral lymph nodes and map phenotypes to the vasculature. We identify multiple subsets, including a medullary venous population whose gene signature predicts a selective role in myeloid cell (vs lymphocyte) recruitment to the medulla, confirmed by videomicroscopy. We define five capillary subsets, including a capillary resident precursor (CRP) that displays stem cell and migratory gene signatures, and contributes to homeostatic BEC turnover and to neogenesis of high endothelium after immunization. Cell alignments show retention of developmental programs along trajectories from CRP to mature venous and arterial populations. Our single cell atlas provides a molecular roadmap of the lymph node blood vasculature and defines subset specialization for leukocyte recruitment and vascular homeostasis.
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http://dx.doi.org/10.1038/s41467-020-17291-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7393069PMC
July 2020

Phenotypical Characterization of Spleen Remodeling in Murine Experimental Visceral Leishmaniasis.

Front Immunol 2020 15;11:653. Epub 2020 Apr 15.

Laboratório de Patologia Estrutural e Molecular, Instituto Gonçalo Moniz, Fundação Oswaldo Cruz, Salvador, Brazil.

Visceral leishmaniasis (VL) is caused by or infection. One of the main problems related to this disease is the emergence of severe clinical forms with a lethality of 5-20%, even while under specific treatment. In humans and other species susceptible to fatal VL, such as dogs and hamsters, the disruption of splenic white pulp (WP) is accompanied by disease progression. Control of VL progression is seen in BALB/c mice, as evidenced by a mild clinical presentation and controlled parasite replication in the liver and spleen. In this study, we investigated the features involved in the morphological remodeling of splenic compartments associated with the control of VL progression to death. We evaluated cohorts of BALB/c mice after 30, 60, and 90 days of infection by . Spleen morphology, cell population subsets and cytokine production were studied in the spleen using flow- and histo-cytometry. Intraperitoneal infection with 10 promastigotes of led to progressive increases in spleen size at 60 and 90 days after infection. Splenomegaly was the only clinical sign of disease observed. At 30 days after infection, hyperplasia in the WP and decreased numbers of plasmacytoid dendritic cells were observed. The WP hyperplasia subsided at 60 days post-infection. However, the splenomegaly remained in association with increased numbers of macrophages, B and T lymphocytes and plasma cells. An increased number of lymphoid tissue inducer (LTi) cells was observed; these were distributed around the periarteriolar lymphoid sheath in control mice and scattered throughout the red pulp in the -infected mice. After 90 days of infection, increased IL-6 and IFN-γ production was seen in the spleen, as well as higher frequencies of follicular and plasmacytoid dendritic cells. The data presented herein emphasizes the potential role of spleen remodeling in the control of severe forms of VL and highlights features potentially involved in this process.
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http://dx.doi.org/10.3389/fimmu.2020.00653DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7174685PMC
April 2020

Stromal cells and immune cells involved in formation of lymph nodes and their niches.

Curr Opin Immunol 2020 Apr 20;64:20-25. Epub 2020 Apr 20.

Amsterdam UMC, VU University of Amsterdam, Department of Molecular Cell Biology and Immunology, Amsterdam Infection and Immunity Institute, Amsterdam, Netherlands. Electronic address:

Secondary lymphoid organs are critical for efficient interaction between innate antigen presenting cells and adaptive lymphocytes in order to start adaptive immune responses. The efficiency by which these cellular subsets meet is highly increased by the orchestrating role of stromal cells within the secondary lymphoid organs. These cells provide cytokines, chemokines and cell surface receptors necessary for survival and guided migration. This increases the likelihood that antigen specific adaptive immune responses occur. Already from initial formation of secondary lymphoid organs, the interaction of immune cells with stromal cells is crucial and this interaction continues during immune activation. With the recent discovery of many stromal cell subsets new immune micro-niches with specific functions that are orchestrated by stromal cells will be discovered. Here, we will discuss how the development of lymph nodes as well as their specific niches is guided by the interaction of immune cells and stromal cells.
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http://dx.doi.org/10.1016/j.coi.2020.03.003DOI Listing
April 2020

Intestinal Macrophages Balance Inflammatory Expression Profiles via Vitamin A and Dectin-1-Mediated Signaling.

Front Immunol 2020 31;11:551. Epub 2020 Mar 31.

Department of Molecular Cell Biology and Immunology, Amsterdam Infection and Immunity Institute, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, Netherlands.

Tissue resident intestinal macrophages are known to exhibit an anti-inflammatory phenotype and produce little pro-inflammatory cytokines upon TLR ligation, allowing symbiotic co-existence with the intestinal microbiota. However, upon acute events such as epithelial damage and concomitant influx of microbes, these macrophages must be able to quickly mount a pro-inflammatory response while more inflammatory macrophages are recruited from the blood stream simultaneously. Here, we show that dietary intake of vitamin A is required for the maintenance of the anti-inflammatory state of tissue resident intestinal macrophages. Interestingly, these anti-inflammatory macrophages were characterized by high levels of Dectin-1 expression. We show that Dectin-1 expression is enhanced by the vitamin A metabolite retinoic acid and our data suggests that Dectin-1 triggering might provide a switch to induce a rapid production of pro-inflammatory cytokines. In addition, Dectin-1 stimulation resulted in an altered metabolic profile which is linked to a pro-inflammatory response. Together, our data suggests that presence of vitamin A in the small intestine enhances an anti-inflammatory phenotype as well as Dectin-1 expression by macrophages and that this anti-inflammatory phenotype can rapidly convert toward a pro-inflammatory state upon Dectin-1 signaling.
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http://dx.doi.org/10.3389/fimmu.2020.00551DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7138104PMC
March 2020

Lymph Node Stromal Cells Generate Antigen-Specific Regulatory T Cells and Control Autoreactive T and B Cell Responses.

Cell Rep 2020 03;30(12):4110-4123.e4

Department of Molecular Cell Biology and Immunology, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam Infection and Immunity Institute, Amsterdam, the Netherlands. Electronic address:

Within lymph nodes (LNs), T follicular helper (T) cells help B cells to produce antibodies, which can either be protective or autoreactive. Here, we demonstrate that murine LN stromal cells (LNSCs) suppress the formation of autoreactive T cells in an antigen-specific manner, thereby significantly reducing germinal center B cell responses directed against the same self-antigen. Mechanistically, LNSCs express and present self-antigens in major histocompatibility complex (MHC) class II, leading to the conversion of naive CD4 T cells into T regulatory (T) cells in an interleukin-2 (IL-2)-dependent manner. Upon blockade of T cells, using neutralizing IL-2 antibodies, autoreactive T cells are allowed to develop. We conclude that the continuous presentation of self-antigens by LNSCs is critical to generate antigen-specific T cells, thereby repressing the formation of T cells and germinal center B cell responses. Our findings uncover the ability of LNSCs to suppress the early activation of autoreactive immune cells and maintain peripheral tolerance.
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http://dx.doi.org/10.1016/j.celrep.2020.03.007DOI Listing
March 2020

Development of a Retinal-Based Probe for the Profiling of Retinaldehyde Dehydrogenases in Cancer Cells.

ACS Cent Sci 2019 Dec 12;5(12):1965-1974. Epub 2019 Dec 12.

Department of Molecular Physiology, Leiden Institute of Chemistry, Leiden University, Leiden 2300 RA, The Netherlands.

Retinaldehyde dehydrogenases belong to a superfamily of enzymes that regulate cell differentiation and are responsible for detoxification of anticancer drugs. Chemical tools and methods are of great utility to visualize and quantify aldehyde dehydrogenase (ALDH) activity in health and disease. Here, we present the discovery of a first-in-class chemical probe based on retinal, the endogenous substrate of retinal ALDHs. We unveil the utility of this probe in quantitating ALDH isozyme activity in a panel of cancer cells via both fluorescence and chemical proteomic approaches. We demonstrate that our probe is superior to the widely used ALDEFLUOR assay to explain the ability of breast cancer (stem) cells to produce retinoic acid. Furthermore, our probe revealed the cellular selectivity profile of an advanced ALDH1A1 inhibitor, thereby prompting us to investigate the nature of its cytotoxicity. Our results showcase the application of substrate-based probes in interrogating pathologically relevant enzyme activities. They also highlight the general power of chemical proteomics in driving the discovery of new biological insights and its utility to guide drug discovery efforts.
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http://dx.doi.org/10.1021/acscentsci.9b01022DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6936097PMC
December 2019

The Role of Endothelial Cells and TNF-Receptor Superfamily Members in Lymphoid Organogenesis and Function During Health and Inflammation.

Front Immunol 2019 20;10:2700. Epub 2019 Nov 20.

Amsterdam Rheumatology and Immunology Center (ARC), Department of Rheumatology and Clinical Immunology, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands.

Lymph nodes (LNs) are crucial for the orchestration of immune responses. LN reactions depend on interactions between incoming and local immune cells, and stromal cells. To mediate these cellular interactions an organized vascular network within the LN exists. In general, the LN vasculature can be divided into two components: blood vessels, which include the specialized high endothelial venules that recruit lymphocytes from the bloodstream, and lymphatic vessels. Signaling via TNF receptor (R) superfamily (SF) members has been implicated as crucial for the development and function of LNs and the LN vasculature. In recent years the role of cell-specific signaling of TNFRSF members in different endothelial cell (EC) subsets and their roles in development and maintenance of lymphoid organs has been elucidated. Here, we discuss recent insights into EC-specific TNFRSF member signaling and highlight its importance in different EC subsets in LN organogenesis and function during health, and in lymphocyte activation and tertiary lymphoid structure formation during inflammation.
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http://dx.doi.org/10.3389/fimmu.2019.02700DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6879661PMC
November 2020

CD62L Is a Functional and Phenotypic Marker for Circulating Innate Lymphoid Cell Precursors.

J Immunol 2019 01 30;202(1):171-182. Epub 2018 Nov 30.

Department of Molecular Cell Biology and Immunology, VU University Medical Center, 1081AZ Amsterdam, the Netherlands;

Innate lymphoid cells (ILCs) guard epithelial tissue integrity during homeostasis, but can be potent immune effector cells during inflammation. Precursors to all ILC subsets (ILC precursors [ILCP]) have been identified in human peripheral blood (PB). We found that during homeostasis, ILCP in PB of mouse and human expressed homing receptors for secondary lymphoid organs, mainly CD62L. These ILCP entered mouse lymph nodes in a CD62L-dependent way and relied on S1P receptors for their exit. Importantly, CD62L expression was absent on human ILCs expressing NKp44 in tonsils and PB of Crohn disease patients, and relatively fewer CD62L ILCP were present in PB of Crohn disease patients. These data are in agreement with selective expression of CD62L on nonactivated ILCP. As such, we conclude that CD62L not only serves as a functional marker of ILCP, but has potential to be used in the clinic as a diagnostic marker in inflammatory disorders.
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http://dx.doi.org/10.4049/jimmunol.1701153DOI Listing
January 2019

Complexity of Lymphoid Tissue Organizers: A Response to Onder and Ludewig.

Trends Immunol 2018 12 2;39(12):951-952. Epub 2018 Nov 2.

Department of Molecular Cell Biology and Immunology, Amsterdam UMC, Vrije Universiteit, Amsterdam, The Netherlands. Electronic address:

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http://dx.doi.org/10.1016/j.it.2018.10.006DOI Listing
December 2018

Innate Lymphoid Cells: 10 Years On.

Cell 2018 08;174(5):1054-1066

Department of Experimental Immunology Academic Medical Center of the University of Amsterdam, Amsterdam, the Netherlands.

Innate lymphoid cells (ILCs) are lymphocytes that do not express the type of diversified antigen receptors expressed on T cells and B cells. ILCs are largely tissue-resident cells and are deeply integrated into the fabric of tissues. The discovery and investigation of ILCs over the past decade has changed our perception of immune regulation and how the immune system contributes to the maintenance of tissue homeostasis. We now know that cytokine-producing ILCs contribute to multiple immune pathways by, for example, sustaining appropriate immune responses to commensals and pathogens at mucosal barriers, potentiating adaptive immunity, and regulating tissue inflammation. Critically, the biology of ILCs also extends beyond classical immunology to metabolic homeostasis, tissue remodeling, and dialog with the nervous system. The last 10 years have also contributed to our greater understanding of the transcriptional networks that regulate lymphocyte commitment and delineation. This, in conjunction with the recent advances in our understanding of the influence of local tissue microenvironments on the plasticity and function of ILCs, has led to a re-evaluation of their existing categorization. In this review, we distill the advances in ILC biology over the past decade to refine the nomenclature of ILCs and highlight the importance of ILCs in tissue homeostasis, morphogenesis, metabolism, repair, and regeneration.
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http://dx.doi.org/10.1016/j.cell.2018.07.017DOI Listing
August 2018

The Microenvironment in Barrett's Esophagus Tissue Is Characterized by High and Levels.

Front Immunol 2018 18;9:1375. Epub 2018 Jun 18.

Laboratory of Translational Immunology, Department of Respiratory Medicine, University Medical Center Utrecht, Utrecht, Netherlands.

Metaplasia in Barrett's esophagus (BE) is characterized by the transition of squamous epithelium into intestinal-type columnar epithelium. The immune response in BE shares many similarities with the response found in the gut, which is different from the response found in a normal-looking esophagus. Here, we investigated the role of the genes associated with the retinoic acid (RA) pathway in BE, as RA is important not only in shaping the gut's immune response but also in the induction of metaplasia . mRNA was isolated from esophageal and duodenal biopsies from BE ( = 14), reflux esophagitis patients ( = 9), and controls ( = 12). cDNA was made and qPCR was performed. The expression of RALDH1, CYP26A1, MAdCAM1 were similar for both the BE and duodenum, but different when compared to squamous esophageal epithelium. BE was characterized by a higher expression of RALDH2 and FOXP3, compared to the duodenum. In BE, RALDH2 correlated with expression of the myeloid dendritic cell-specific genes: CD11c and CD1c. Also, RALDH2 expression correlated with RAR-β and FOXP3. Hierarchical clustering on the expression of multiple relevant genes demonstrated that BE, duodenum, and SQ tissues are clustered as three different groups. The differential expression of RA-specific genes and dendritic cell (DC)-subsets indicates that BE resembles duodenal tissue. The higher expression of RALDH2 and FOXP3 in BE points at a mechanism associated with a possible anti-inflammatory microenvironment. This aberrant immune regulation might contribute to the altered tissue and immune responses found in BE.
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http://dx.doi.org/10.3389/fimmu.2018.01375DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6015910PMC
June 2018

Impaired lymph node stromal cell function during the earliest phases of rheumatoid arthritis.

Arthritis Res Ther 2018 02 26;20(1):35. Epub 2018 Feb 26.

Amsterdam Rheumatology & immunology Centre (ARC), Department of Clinical Immunology and Rheumatology, Academic Medical Centre, University of Amsterdam, Meibergdreef 9, Amsterdam, 1105, AZ, the Netherlands.

Background: Systemic autoimmunity can be present years before clinical onset of rheumatoid arthritis (RA). Adaptive immunity is initiated in lymphoid tissue where lymph node stromal cells (LNSCs) regulate immune responses through their intimate connection with leucocytes. We postulate that malfunctioning of LNSCs creates a microenvironment in which normal immune responses are not properly controlled, possibly leading to autoimmune disease. In this study we established an experimental model for studying the functional capacities of human LNSCs during RA development.

Methods: Twenty-four patients with RA, 23 individuals positive for autoantibodies but without clinical disease (RA risk group) and 14 seronegative healthy control subjects underwent ultrasound-guided inguinal lymph node (LN) biopsy. Human LNSCs were isolated and expanded in vitro for functional analyses. In analogous co-cultures consisting of LNSCs and peripheral blood mononuclear cells, αCD3/αCD28-induced T-cell proliferation was measured using carboxyfluorescein diacetate succinimidyl ester dilution.

Results: Fibroblast-like cells expanded from the LN biopsy comprised of fibroblastic reticular cells (gp38CD31) and double-negative (gp38CD31) cells. Cultured LNSCs stably expressed characteristic adhesion molecules and cytokines. Basal expression of C-X-C motif chemokine ligand 12 (CXCL12) was lower in LNSCs from RA risk individuals than in those from healthy control subjects. Key LN chemokines C-C motif chemokine ligand (CCL19), CCL21 and CXCL13 were induced in LNSCs upon stimulation with tumour necrosis factor-α and lymphotoxin αβ, but to a lesser extent in LNSCs from patients with RA. The effect of human LNSCs on T-cell proliferation was ratio-dependent and altered in RA LNSCs.

Conclusions: Overall, we developed an experimental model to facilitate research on the role of LNSCs during the earliest phases of RA. Using this innovative model, we show, for the first time to our knowledge, that the LN stromal environment is changed during the earliest phases of RA, probably contributing to deregulated immune responses early in disease pathogenesis.
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http://dx.doi.org/10.1186/s13075-018-1529-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5828373PMC
February 2018

Dendritic Cell Migration to Skin-Draining Lymph Nodes Is Controlled by Dermatan Sulfate and Determines Adaptive Immunity Magnitude.

Front Immunol 2018 8;9:206. Epub 2018 Feb 8.

Department of Molecular Cell Biology and Immunology, VU University Medical Center, Cancer Center Amsterdam, Amsterdam, Netherlands.

For full activation of naïve adaptive lymphocytes in skin-draining lymph nodes (LNs), presentation of peptide:MHC complexes by LN-resident and skin-derived dendritic cells (DCs) that encountered antigens (Ags) is an absolute prerequisite. To get to the nearest draining LN upon intradermal immunization, DCs need to migrate from the infection site to the afferent lymphatics, which can only be reached by traversing a collagen-dense network located in the dermis of the skin through the activity of proteolytic enzymes. Here, we show that mice with altered collagen fibrillogenesis resulting in thicker collagen fibers in the skin display a reduced DC migration to the draining LN upon immune challenge. Consequently, the initiation of the cellular and humoral immune response was diminished. Ag-specific CD8+ and CD4+ T cells as well as Ag-specific germinal center B cells and serum immunoglobulin levels were significantly decreased. Hence, we postulate that alterations to the production of extracellular matrix, as seen in various connective tissue disorders, may in the end affect the qualitative outcome of adaptive immunity.
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http://dx.doi.org/10.3389/fimmu.2018.00206DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5809438PMC
April 2019

Cross-Tissue Transcriptomic Analysis of Human Secondary Lymphoid Organ-Residing ILC3s Reveals a Quiescent State in the Absence of Inflammation.

Cell Rep 2017 Oct;21(3):823-833

Department of Hematology, Erasmus University Medical Center, 3000 CA Rotterdam, the Netherlands. Electronic address:

A substantial number of human and mouse group 3 innate lymphoid cells (ILC3s) reside in secondary lymphoid organs, yet the phenotype and function of these ILC3s is incompletely understood. Here, we employed an unbiased cross-tissue transcriptomic approach to compare human ILC3s from non-inflamed lymph nodes and spleen to their phenotypic counterparts in inflamed tonsils and from circulation. These analyses revealed that, in the absence of inflammation, lymphoid organ-residing ILC3s lack transcription of cytokines associated with classical ILC3 functions. This was independent of expression of the natural cytotoxicity receptor NKp44. However, and in contrast to ILC3s from peripheral blood, lymphoid organ-residing ILC3s express activating cytokine receptors and have acquired the ability to be recruited into immune responses by inflammatory cytokines. This comprehensive cross-tissue dataset will allow for identification of functional changes in human lymphoid organ ILC3s associated with human disease.
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http://dx.doi.org/10.1016/j.celrep.2017.09.070DOI Listing
October 2017

Neuropilin-1 Is Expressed on Lymphoid Tissue Residing LTi-like Group 3 Innate Lymphoid Cells and Associated with Ectopic Lymphoid Aggregates.

Cell Rep 2017 02;18(7):1761-1773

Department of Experimental Medicine, Academic Medical Center, University of Amsterdam, 1105 AZ Amsterdam, the Netherlands. Electronic address:

Here, we characterize a subset of ILC3s that express Neuropilin1 (NRP1) and are present in lymphoid tissues, but not in the peripheral blood or skin. NRP1 group 3 innate lymphoid cells (ILC3s) display in vitro lymphoid tissue inducer (LTi) activity. In agreement with this, NRP1 ILC3s are mainly located in proximity to high endothelial venules (HEVs) and express cell surface molecules involved in lymphocyte migration in secondary lymphoid tissues via HEVs. NRP1 was also expressed on mouse fetal LTi cells, indicating that NRP1 is a conserved marker for LTi cells. Human NRP1 ILC3s are primed cells because they express CD45RO and produce higher amounts of cytokines than NRP1 cells, which express CD45RA. The NRP1 ligand vascular endothelial growth factor A (VEGF-A) served as a chemotactic factor for NRP1 ILC3s. NRP1 ILC3s are present in lung tissues from smokers and patients with chronic obstructive pulmonary disease, suggesting a role in angiogenesis and/or the initiation of ectopic pulmonary lymphoid aggregates.
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http://dx.doi.org/10.1016/j.celrep.2017.01.063DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5318658PMC
February 2017

Diet-Derived Short Chain Fatty Acids Stimulate Intestinal Epithelial Cells To Induce Mucosal Tolerogenic Dendritic Cells.

J Immunol 2017 03 18;198(5):2172-2181. Epub 2017 Jan 18.

Department of Molecular Cell Biology and Immunology, VU University Medical Center, 1081 HZ Amsterdam, the Netherlands;

The gastrointestinal tract is continuously exposed to many environmental factors that influence intestinal epithelial cells and the underlying mucosal immune system. In this article, we demonstrate that dietary fiber and short chain fatty acids (SCFAs) induced the expression of the vitamin A-converting enzyme RALDH1 in intestinal epithelial cells in vivo and in vitro, respectively. Furthermore, our data showed that the expression levels of RALDH1 in small intestinal epithelial cells correlated with the activity of vitamin A-converting enzymes in mesenteric lymph node dendritic cells, along with increased numbers of intestinal regulatory T cells and a higher production of luminal IgA. Moreover, we show that the consumption of dietary fiber can alter the composition of SCFA-producing microbiota and SCFA production in the small intestines. In conclusion, our data illustrate that dietary adjustments affect small intestinal epithelial cells and can be used to modulate the mucosal immune system.
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http://dx.doi.org/10.4049/jimmunol.1600165DOI Listing
March 2017

Retinoic Acid and Immune Homeostasis: A Balancing Act.

Trends Immunol 2017 03 13;38(3):168-180. Epub 2017 Jan 13.

Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands. Electronic address:

In the immune system, the vitamin A metabolite retinoic acid (RA) is known for its role in inducing gut-homing molecules in T and B cells, inducing regulatory T cells (Tregs), and promoting tolerance. However, it was suggested that RA can have a broad spectrum of effector functions depending on the local microenvironment. Under specific conditions, RA can also promote an inflammatory environment. We discuss the dual role of RA in immune responses and how this might be regulated. Furthermore, we focus on the role of RA in autoimmune diseases and whether RA might be used as a therapeutic agent.
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http://dx.doi.org/10.1016/j.it.2016.12.006DOI Listing
March 2017

A Reproducible Method for Isolation and In Vitro Culture of Functional Human Lymphoid Stromal Cells from Tonsils.

PLoS One 2016 1;11(12):e0167555. Epub 2016 Dec 1.

Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands.

The stromal compartment of secondary lymphoid organs is classicaly known for providing a mechanical scaffold for the complex interactions between hematopoietic cells during immune activation as well as for providing a niche which is favorable for survival of lymphocytes. In recent years, it became increasingly clear that these cells also play an active role during such a response. Currently, knowledge of the interactions between human lymphoid stroma and hematopoietic cells is still lacking and most insight is based on murine systems. Although methods to isolate stromal cells from tonsils have been reported, data on stability in culture, characterization, and functional properties are lacking. Here, we describe a reproducible and easy method for isolation and in vitro culture of functional human lymphoid stromal cells from palatine tonsils. The cells isolated express markers and characteristics of T cell zone fibroblastic reticular cells (FRCs) and react to inflammatory stimuli by upregulating inflammatory cytokines and chemokines as well as adhesion molecules, as previously described for mouse lymphoid stroma. Also, cultured tonsil stromal cells support survival of human innate lymphoid cells, showing that these stromal cells can function as bone fide FRCs, providing a favorable microenvironment for hematopoietic cells.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0167555PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5132289PMC
June 2017

Nestin-Expressing Precursors Give Rise to Both Endothelial as well as Nonendothelial Lymph Node Stromal Cells.

J Immunol 2016 10 29;197(7):2686-94. Epub 2016 Aug 29.

Department of Molecular Cell Biology and Immunology, VU University Medical Center, 1081 HZ Amsterdam, the Netherlands;

During embryogenesis, lymph nodes form through intimate interaction between lymphoid tissue inducer and lymphoid tissue organizer (LTo) cells. Shortly after birth in mice, specialized stromal cell subsets arise that organize microenvironments within the lymph nodes; however, their direct precursors have not yet been identified. In the bone marrow, mesenchymal stem cells are labeled with GFP in nestin-GFP mice, and we show that during all stages of development, nestin(+) cells are present within lymph nodes of these mice. At day of birth, both mesenchymal CD31(-) and endothelial CD31(+) LTo cells were GFP(+), and only the population of CD31(-) LTo cells contained mesenchymal precursors. These CD31(-)nestin(+) cells are found in the T and B cell zones or in close association with high endothelial venules in adult lymph nodes. Fate mapping of nestin(+) cells unambiguously revealed the contribution of nestin(+) precursor cells to the mesenchymal as well as the endothelial stromal populations within lymph nodes. However, postnatal tamoxifen induced targeting of nestin(+) cells in nes-creER mice showed that most endothelial cells and only a minority of the nonendothelial cells were labeled. Overall our data show that nestin(+) cells contribute to all subsets of the complex stromal populations that can be found in lymph nodes.
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http://dx.doi.org/10.4049/jimmunol.1501162DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5459591PMC
October 2016

Vagal innervation is required for the formation of tertiary lymphoid tissue in colitis.

Eur J Immunol 2016 10 18;46(10):2467-2480. Epub 2016 Aug 18.

Department of Molecular Cell Biology and Immunology, Vrije Universiteit Medical Center, Amsterdam, The Netherlands.

Tertiary lymphoid tissue (TLT) is lymphoid tissue that forms in adult life as a result of chronic inflammation in a tissue or organ. TLT has been shown to form in a variety of chronic inflammatory diseases, though it is not clear if and how TLT develops in the inflamed colon during inflammatory bowel disease. Here, we show that TLT develops as newly formed lymphoid tissue in the colon following dextran sulphate sodium induced colitis in C57BL/6 mice, where it can be distinguished from the preexisting colonic patches and solitary intestinal lymphoid tissue. TLT in the inflamed colon develops following the expression of lymphoid tissue-inducing chemokines and adhesion molecules, such as CXCL13 and VCAM-1, respectively, which are produced by stromal organizer cells. Surprisingly, this process of TLT formation was independent of the lymphotoxin signaling pathway, but rather under neuronal control, as we demonstrate that selective surgical ablation of vagus nerve innervation inhibits CXCL13 expression and abrogates TLT formation without affecting colitis. Sympathetic neuron denervation does not affect TLT formation. Hence, we reveal that inflammation in the colon induces the formation of TLT, which is controlled by innervation through the vagus nerve.
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http://dx.doi.org/10.1002/eji.201646370DOI Listing
October 2016

Dietary Fiber and Bacterial SCFA Enhance Oral Tolerance and Protect against Food Allergy through Diverse Cellular Pathways.

Cell Rep 2016 06;15(12):2809-24

Infection and Immunity Program, Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800, Australia; Charles Perkins Centre, The University of Sydney, Sydney, NSW 2006, Australia; Department of Physiology, Faculty of Medicine, The University of Sydney, Sydney, NSW 2006, Australia. Electronic address:

The incidence of food allergies in western countries has increased dramatically in recent decades. Tolerance to food antigens relies on mucosal CD103(+) dendritic cells (DCs), which promote differentiation of regulatory T (Treg) cells. We show that high-fiber feeding in mice improved oral tolerance and protected from food allergy. High-fiber feeding reshaped gut microbial ecology and increased the release of short-chain fatty acids (SCFAs), particularly acetate and butyrate. High-fiber feeding enhanced oral tolerance and protected against food allergy by enhancing retinal dehydrogenase activity in CD103(+) DC. This protection depended on vitamin A in the diet. This feeding regimen also boosted IgA production and enhanced T follicular helper and mucosal germinal center responses. Mice lacking GPR43 or GPR109A, receptors for SCFAs, showed exacerbated food allergy and fewer CD103(+) DCs. Dietary elements, including fiber and vitamin A, therefore regulate numerous protective pathways in the gastrointestinal tract, necessary for immune non-responsiveness to food antigens.
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http://dx.doi.org/10.1016/j.celrep.2016.05.047DOI Listing
June 2016

Vitamin A Controls the Presence of RORγ+ Innate Lymphoid Cells and Lymphoid Tissue in the Small Intestine.

J Immunol 2016 06 9;196(12):5148-55. Epub 2016 May 9.

Department of Molecular Cell Biology and Immunology, VU University Medical Center, 1081 BT Amsterdam, the Netherlands; and

Changes in diet and microbiota have determining effects on the function of the mucosal immune system. For example, the active metabolite of vitamin A, retinoic acid (RA), has been described to maintain homeostasis in the intestine by its influence on both lymphocytes and myeloid cells. Additionally, innate lymphoid cells (ILCs), important producers of cytokines necessary for intestinal homeostasis, are also influenced by vitamin A in the small intestines. In this study, we show a reduction of both NCR(-) and NCR(+) ILC3 subsets in the small intestine of mice raised on a vitamin A-deficient diet. Additionally, the percentages of IL-22-producing ILCs were reduced in the absence of dietary vitamin A. Conversely, mice receiving additional RA had a specific increase in the NCR(-) ILC3 subset, which contains the lymphoid tissue inducer cells. The dependence of lymphoid tissue inducer cells on vitamin A was furthermore illustrated by impaired development of enteric lymphoid tissues in vitamin A-deficient mice. These effects were a direct consequence of ILC-intrinsic RA signaling, because retinoic acid-related orphan receptor γt-Cre × RARα-DN mice had reduced numbers of NCR(-) and NCR(+) ILC3 subsets within the small intestine. However, lymphoid tissue inducer cells were not affected in these mice nor was the formation of enteric lymphoid tissue, demonstrating that the onset of RA signaling might take place before retinoic acid-related orphan receptor γt is expressed on lymphoid tissue inducer cells. Taken together, our data show an important role for vitamin A in controlling innate lymphoid cells and, consequently, postnatal formed lymphoid tissues within the small intestines.
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http://dx.doi.org/10.4049/jimmunol.1501106DOI Listing
June 2016

Innate lymphoid cells in secondary lymphoid organs.

Immunol Rev 2016 May;271(1):185-99

Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, The Netherlands.

The family of innate lymphoid cells (ILCs) has attracted attention in recent years as its members are important regulators of immunity, while they can also cause pathology. In both mouse and man, ILCs were initially discovered in developing lymph nodes as lymphoid tissue inducer (LTi) cells. These cells form the prototypic members of the ILC family and play a central role in the formation of secondary lymphoid organs (SLOs). In the absence of LTi cells, lymph nodes (LN) and Peyer's Patches (PP) fail to form in mice, although the splenic white pulp can develop normally. Besides LTi cells, the ILC family encompasses helper-like ILCs with functional distinctions as seen by T-helper cells, as well as cytotoxic natural killer (NK) cells. ILCs are still present in adult SLOs where they have been shown to play a role in lymphoid tissue regeneration. Furthermore, ILCs were implicated to interact with adaptive lymphocytes and influence the adaptive immune response. Here, we review the recent literature on the role of ILCs in secondary lymphoid tissue from the formation of SLOs to mature SLOs in adults, during homeostasis and pathology.
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http://dx.doi.org/10.1111/imr.12407DOI Listing
May 2016

Fungi Take Control of Lymphocyte Recirculation.

Immunity 2016 Feb;44(2):211-3

Department of Molecular Cell Biology and Immunology, VU University Medical Center, 1081 HZ Amsterdam, the Netherlands. Electronic address:

Factors regulating leukocyte migration to neonatal lymph nodes are not sufficiently identified. In this issue of Immunity, Zhang et al. (2016) reveal that fungi drive emigration of gut DCs to lymph nodes, where these DCs instruct endothelial cell receptivity to leukocytes.
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http://dx.doi.org/10.1016/j.immuni.2016.01.017DOI Listing
February 2016

Identification of natural RORγ ligands that regulate the development of lymphoid cells.

Cell Metab 2015 Feb;21(2):286-298

The Kimmel Center for Biology and Medicine of the Skirball Institute, New York University School of Medicine, New York, NY 10016, USA; Howard Hughes Medical Institute, New York University School of Medicine, New York, NY 10016, USA.

Mice deficient in the nuclear hormone receptor RORγt have defective development of thymocytes, lymphoid organs, Th17 cells, and type 3 innate lymphoid cells. RORγt binds to oxysterols derived from cholesterol catabolism, but it is not clear whether these are its natural ligands. Here, we show that sterol lipids are necessary and sufficient to drive RORγt-dependent transcription. We combined overexpression, RNAi, and genetic deletion of metabolic enzymes to study RORγ-dependent transcription. Our results are consistent with the RORγt ligand(s) being a cholesterol biosynthetic intermediate (CBI) downstream of lanosterol and upstream of zymosterol. Analysis of lipids bound to RORγ identified molecules with molecular weights consistent with CBIs. Furthermore, CBIs stabilized the RORγ ligand-binding domain and induced coactivator recruitment. Genetic deletion of metabolic enzymes upstream of the RORγt-ligand(s) affected the development of lymph nodes and Th17 cells. Our data suggest that CBIs play a role in lymphocyte development potentially through regulation of RORγt.
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http://dx.doi.org/10.1016/j.cmet.2015.01.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4317570PMC
February 2015

50 years of Dutch immunology--founders, institutions, highlights.

Immunol Lett 2014 Dec 16;162(2 Pt B):85-94. Epub 2014 Oct 16.

Department of Molecular Cell Biology and Immunology, VU University Medical Center, Van der Boechorststraat 7, 1081 BT Amsterdam, The Netherlands. Electronic address:

At the occasion of the 50th anniversary of the Dutch Society for Immunology (DSI, de Nederlandse Vereniging voor Immunologie), this contribution deals with some highlights of 50 years of Immunology in the Netherlands. It narrates about the founders and first board members of the DSI, their institutes, progeny and patrimony, describes major centers of immunological activities, mentions key persons in the field, and touches upon some events dear to the Society and its members.
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http://dx.doi.org/10.1016/j.imlet.2014.10.014DOI Listing
December 2014

Lymph node stromal cells constrain immunity via MHC class II self-antigen presentation.

Elife 2014 Nov 19;3. Epub 2014 Nov 19.

Department of Molecular Cell Biology and Immunology, Vrije Universiteit Medical Center, Amsterdam, Netherlands.

Non-hematopoietic lymph node stromal cells shape immunity by inducing MHC-I-dependent deletion of self-reactive CD8 T cells and MHC-II-dependent anergy of CD4 T cells. In this study, we show that MHC-II expression on lymph node stromal cells is additionally required for homeostatic maintenance of regulatory T cells (Tregs) and maintenance of immune quiescence. In the absence of MHC-II expression in lymph node transplants, i.e. on lymph node stromal cells, CD4 as well as CD8 T cells became activated, ultimately resulting in transplant rejection. MHC-II self-antigen presentation by lymph node stromal cells allowed the non-proliferative maintenance of antigen-specific Tregs and constrained antigen-specific immunity. Altogether, our results reveal a novel mechanism by which lymph node stromal cells regulate peripheral immunity.
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http://dx.doi.org/10.7554/eLife.04433DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4270074PMC
November 2014

Vitamin A metabolism and mucosal immune function are distinct between BALB/c and C57BL/6 mice.

Eur J Immunol 2015 Jan 17;45(1):89-100. Epub 2014 Nov 17.

Department of Molecular Cell Biology and Immunology, VU medical center, Amsterdam, The Netherlands.

The vitamin A metabolite retinoic acid (RA) has been reported to suppress Th1 responses and enhance Th2 responses. Here, we investigated whether differences in vitamin A metabolism could underlie the differences between C57BL/6 and BALB/c mice, which are reportedly seen as Th1 and Th2 responders, respectively. BALB/c mice were shown to have higher intestinal epithelial expression of RALDH1 (where RALDH is retinaldehyde dehydrogenase), and, consequently, higher RALDH activity in MLN-DCs, leading to an increased ability to induce IgA class switching in B cells. Furthermore, within BALB/c mice, induction of IgA secretion as well as increased accumulation of regulatory T cells (Treg) in the intestinal lamina propria was observed. Additionally, as BALB/c mice are more resistant to dextran sulphate sodium (DSS) induced colitis, mice that lacked vitamin A in their diet had a more severe form of DSS-induced colitis compared to control mice. Therefore, the level of RA production and consequently the degree of RA-mediated signaling is crucial for the efficiency of the mucosal immune system.
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http://dx.doi.org/10.1002/eji.201343340DOI Listing
January 2015