Publications by authors named "Yanling Xiao"

37 Publications

People Living with HIV Easily lose their Immune Response to SARS-CoV-2: Result From A Cohort of COVID-19 Cases in Wuhan, China.

Res Sq 2021 Jun 7. Epub 2021 Jun 7.

Background To date, whether the immune response for SARS-CoV-2 infection among people living with HIV(PLWH) is different from HIV-naïve individuals is still not clear. Methods In this cohort study, COVID-19 patients admitted to hospital in Wuhan between January 15 and April 1, 2020, were enrolled. Patients were categorized into PLWH and HIV-naïve group. All patients were followed up regularly (every fifteen days) until November 30, 2020, and the immune response towards SARS-CoV-2 was observed. Results Totally, 18 PLWH and 185 HIV-naïve individuals with COVID-19 were enrolled. The positive conversion rates of IgG were 56% in PLWH and 88% in HIV-naïve patients respectively, and the peak was on the 45th day after COVID-19 onset. However, the positive rate of IgG dropped to 12% in PLWH and 33% among HIV-naïve individuals by the end of the study. The positive conversion rate of IgG among asymptomatic carriers is significantly lower than that among moderate patients (AOR = 0.18, 95% CI: 0.05-0.65) and PLWH had a lower IgG seroconversion rate compared to the HIV-naive group (AOR = 0.22, 95% CI: 0.05-0.90). Patients with lower lymphocyte counts at onset had a higher positive conversion rate (AOR = 0.29, 95% CI: 0.09-0.90) and longer duration for IgG (AHR = 4.01, 95% CI: 1.78-9.02). Conclusions The positive conversion rate of IgG for SARS-CoV-2 was relatively lower and quickly lost in PLWH, which meant PLWH was in a disadvantaged situation when affected with COVID-19.
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http://dx.doi.org/10.21203/rs.3.rs-543375/v1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8202430PMC
June 2021

Flagellin/TLR5 Stimulate Myeloid Progenitors to Enter Lung Tissue and to Locally Differentiate Into Macrophages.

Front Immunol 2021 19;12:621665. Epub 2021 Mar 19.

Division of Tumor Biology and Immunology, The Netherlands Cancer Institute, Amsterdam, Netherlands.

Toll-like receptor 5 (TLR5) is the receptor of bacterial Flagellin. Reportedly, TLR5 engagement helps to combat infections, especially at mucosal sites, by evoking responses from epithelial cells and immune cells. Here we report that TLR5 is expressed on a previously defined bipotent progenitor of macrophages (MΦs) and osteoclasts (OCs) that resides in the mouse bone marrow (BM) and circulates at low frequency in the blood. , Flagellin promoted the generation of MΦs, but not OCs from this progenitor. , MΦ/OC progenitors were recruited from the blood into the lung upon intranasal inoculation of Flagellin, where they rapidly differentiated into MΦs. Recruitment of the MΦ/OC progenitors into the lung was likely promoted by the CCL2/CCR2 axis, since the progenitors expressed CCR2 and type 2 alveolar epithelial cells (AECs) produced CCL2 upon stimulation by Flagellin. Moreover, CCR2 blockade reduced migration of the MΦ/OC progenitors toward lung lavage fluid (LLF) from Flagellin-inoculated mice. Our study points to a novel role of the Flagellin/TLR5 axis in recruiting circulating MΦ/OC progenitors into infected tissue and stimulating these progenitors to locally differentiate into MΦs. The progenitor pathway to produce MΦs may act, next to monocyte recruitment, to fortify host protection against bacterial infection at mucosal sites.
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http://dx.doi.org/10.3389/fimmu.2021.621665DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8017192PMC
March 2021

Clinically applicable CD34-derived blood dendritic cell subsets exhibit key subset-specific features and potently boost anti-tumor T and NK cell responses.

Cancer Immunol Immunother 2021 Apr 1. Epub 2021 Apr 1.

Department of Laboratory Medicine, Laboratory of Hematology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Geert Grooteplein 8, P.O. Box 9101, 6500 HB, Nijmegen, The Netherlands.

Allogeneic stem cell transplantation (alloSCT), following induction chemotherapy, can be curative for hemato-oncology patients due to powerful graft-versus-tumor immunity. However, disease recurrence remains the major cause of treatment failure, emphasizing the need for potent adjuvant immunotherapy. In this regard, dendritic cell (DC) vaccination is highly attractive, as DCs are the key orchestrators of innate and adaptive immunity. Natural DC subsets are postulated to be more powerful compared with monocyte-derived DCs, due to their unique functional properties and cross-talk capacity. Yet, obtaining sufficient numbers of natural DCs, particularly type 1 conventional DCs (cDC1s), is challenging due to low frequencies in human blood. We developed a clinically applicable culture protocol using donor-derived G-CSF mobilized CD34 hematopoietic progenitor cells (HPCs) for simultaneous generation of high numbers of cDC1s, cDC2s and plasmacytoid DCs (pDCs). Transcriptomic analyses demonstrated that these ex vivo-generated DCs highly resemble their in vivo blood counterparts. In more detail, we demonstrated that the CD141CLEG9A cDC1 subset exhibited key features of in vivo cDC1s, reflected by high expression of co-stimulatory molecules and release of IL-12p70 and TNF-α. Furthermore, cDC1s efficiently primed alloreactive T cells, potently cross-presented long-peptides and boosted expansion of minor histocompatibility antigen-experienced T cells. Moreover, they strongly enhanced NK cell activation, degranulation and anti-leukemic reactivity. Together, we developed a robust culture protocol to generate highly functional blood DC subsets for in vivo application as tailored adjuvant immunotherapy to boost innate and adaptive anti-tumor immunity in alloSCT patients.
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http://dx.doi.org/10.1007/s00262-021-02899-3DOI Listing
April 2021

Niobium and Titanium Carbides (MXenes) as Superior Photothermal Supports for CO Photocatalysis.

ACS Nano 2021 Mar 24;15(3):5696-5705. Epub 2021 Feb 24.

Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Soochow University, Suzhou 215123, PR China.

The conversion of CO into fuels and feedstock chemicals photothermal catalysis holds promise for efficient solar energy utilization to tackle the global energy shortage and climate change. Despite recent advances, it is of emerging interest to explore promising materials with excellent photothermal properties to boost the performance of photothermal CO catalysis. Here, we report the discovery of MXene materials as superior photothermal supports for metal nanoparticles. As a proof-of-concept study, we demonstrate that NbC and TiC, two typical MXene materials, can enhance the photothermal effect and thus boost the photothermal catalytic activity of Ni nanoparticles. A record CO conversion rate of 8.50 mol·g·h is achieved for NbC-nanosheet-supported Ni nanoparticles under intense illumination. Our study bridges the gap between photothermal MXene materials and photothermal CO catalysis toward more efficient solar-to-chemical energy conversions and stimulates the interest in MXene-supported metal nanoparticles for other heterogeneous catalytic reactions, particularly driven by sunlight.
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http://dx.doi.org/10.1021/acsnano.1c00990DOI Listing
March 2021

Guizhi Fuling wan for chronic pelvic inflammatory disease protocol: A protocol for systematic review and meta analysis.

Medicine (Baltimore) 2020 Dec;99(51):e23549

College of Basic Medicine, Chengdu University of Traditional Chinese Medicine, Chengdu, Sichuan, China.

Background: Chronic pelvic inflammatory disease (CPID) is one of common diseases of department of gynaecology, point to female inside genital and circumferential organization to suffer from infection of all sorts of pathogenic bacteria and cause chronic inflammation sex disease, also cause one of main factors of infertile of female of childbearing age period. Due to its insidious onset, it is not easy to find out in the early stage. Therefore, it is difficult to obtain satisfactory curative effect by taking routine treatment with antibiotics. In recent years, TCM has made great strides in the treatment of chronic pelvic inflammation, a number of clinical studies have shown that Guizhi Fuling wan combined with antibiotics can significantly improve the clinical symptoms and enhance the therapeutic effect. Therefore, we intend to conduct a system review and meta-analysis to further clarify the effectiveness and safety of GZFLW for CPID.

Methods: We will search each database from the built-in until September2020.The English literature mainly searches Cochrane Library, PubMed, EMBASE, and Web of Science, while the Chinese literature comes from CNKI, CBM, VIP, and Wangfang database. Simultaneously we will retrieval clinical registration tests and grey literatures. This study only screens the clinical randomized controlled trials (RCTs) about GZFLW for CPID to assess its efficacy and safety. The 2 researchers worked independently on literature selection, data extraction, and quality assessment. The dichotomous data is represented by relative risk (RR), and the continuous is expressed by mean difference (MD) or standard mean difference (SMD), eventually the data is synthesized using a fixed effect model (FEM) or a random effect model (REM) depending on whether or not heterogeneity exists. The clinical efficacy, pelvic effusion and mass were evaluated as the main outcomes. The serum interleukin-6 (IL-6), C-reactive protein (CRP), tumor necrosis factor (TNF)-α, erythrocyte sedimentation rate (ESR), erythrocyte specific volume was secondary outcomes. Finally, meta-analysis was conducted by RevMan software version 5.3.

Results: This study will provide high-quality evidence for treatment of CPID with GZFLW in terms of effectiveness and safety.

Conclusion: This systematic review aims to provide new options for GZFLW treatment of CPID in terms of its efficacy and safety.

Ethics And Dissemination: This study does not require ethical approval. We will disseminate our findings by publishing results in a peer-reviewed journal.

Osf Registration Number: DOI 10.17605 / OSF.IO / R9NVT.
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http://dx.doi.org/10.1097/MD.0000000000023549DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7748215PMC
December 2020

Water-Surface Drag Coating: A New Route Toward High-Quality Conjugated Small-Molecule Thin Films with Enhanced Charge Transport Properties.

Adv Mater 2021 Feb 18;33(5):e2005915. Epub 2020 Dec 18.

Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Soochow University, Suzhou, Jiangsu, 215123, P. R. China.

Electronic properties of organic semiconductor (OSC) thin films are largely determined by their morphologies and crystallinities. However, solution-processed conjugated small-molecule OSC thin films usually exhibit abundant grain boundaries and impure grain orientations because of complex fluid dynamics during solution coating. Here, a novel methodology, water-surface drag coating, is demonstrated to fabricate high-quality OSC thin films with greatly enhanced charge transport properties. This method utilizes the water surface to alter the evaporation dynamics of solution to enlarge the grain size, and a unique drag-coating process to achieve the unidirectional growth of organic crystals. Using 2,8-difluoro-5,11-bis(triethylsilylethynyl)anthradithiophene (Dif-TES-ADT) as an example, thin films with millimeter-sized single-crystal domains and pure crystallographic orientations are achieved, revealing a significant enhancement (4.7 times) of carrier mobility. More importantly, the resulting film can be directly transferred onto any desired flexible substrates, and flexible transistors based on the Dif-TES-ADT thin films show a mobility as high as 16.1 cm V s , which represents the highest mobility value for the flexible transistors reported thus far. The method is general for the growth of various high-quality OSC thin films, thus opening up opportunities for high-performance organic flexible electronics.
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http://dx.doi.org/10.1002/adma.202005915DOI Listing
February 2021

A New Medial-to-Lateral Approach for Laparoscopic D3 Lymphadenectomy plus Complete Mesocolic Excision (D3 + CME) for Right-Sided Colon Cancer.

Ann Surg Oncol 2021 Jun 1;28(6):3256-3257. Epub 2020 Nov 1.

Department of Gastrointestinal Surgery, Suining Central Hospital, Suining, Sichuan, China.

Background: D3 lymphadenectomy is important for accurate staging and provides long-term benefits, especially for T3-4/N + tumors.1,2 Both D3 lymphadenectomy as well as complete mesocolic excision (CME) require central ligation of vessels at their origins to ensure radical resection.3 Currently, superior mesentery vein (SMV) is navigated by ileocolic vessels while its sheath is dissected stepwise from caudal to cranial.4-6 This report describes a new medial-to-lateral approach for laparoscopic right hemicolectomy with D3 + CME.

Methods: The patient was a 47-year-old man with diagnosis of hepatic flexure cancer (cT4N1M0). First, the pedicle of the middle colic vessels and ileocolic vessels were both grasped, then the sheath of SMV was dissected at its left side as there are fewer blood vessels entering here compared with its right side. Second, after identification of middle colic artery (MCA), SMV was skeletonized from medial to lateral and no. 213 and no. 203 lymph nodes were dissected. Third, MCA and ileocolic vein and artery (ICV and ICA) were ligated at their roots. After separating the transverse mesocolon from the duodenum, the branches of the Henle trunk were exposed and no. 223 lymph nodes were dissected. Accessory right colic vein, right colic vein, and middle colic vein were ligated respectively. Fourth, the ascending mesocolon was separated from the retroperitoneal tissues through the front side of Toldt's fascia, the mesocolon was mobilized completely, and the tumor was removed en bloc.

Results: The operation time was 175 min, with estimated blood loss of 50 ml. The patient recovered well without bleeding complications and was discharged on postoperative day 7. Histology revealed moderately differentiated adenocarcinoma with 5 of 24 lymph nodes involved (pT3N2M0).

Conclusions: The medial-to-lateral approach presented in the video might be helpful for standardization of laparoscopic D3 + CME for right-sided colon cancer.
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http://dx.doi.org/10.1245/s10434-020-09264-1DOI Listing
June 2021

Bone marrow-derived myeloid progenitors as driver mutation carriers in high- and low-risk Langerhans cell histiocytosis.

Blood 2020 11;136(19):2188-2199

Department of Tumor Biology and Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.

Langerhans cell histiocytosis (LCH) is a myeloid neoplasia, driven by sporadic activating mutations in the MAPK pathway. The misguided myeloid dendritic cell (DC) model proposes that high-risk, multisystem, risk-organ-positive (MS-RO+) LCH results from driver mutation in a bone marrow (BM)-resident multipotent hematopoietic progenitor, while low-risk, MS-RO- and single-system LCH would result from driver mutation in a circulating or tissue-resident, DC-committed precursor. We have examined the CD34+c-Kit+Flt3+ myeloid progenitor population as potential mutation carrier in all LCH disease manifestations. This population contains oligopotent progenitors of monocytes (Mo's)/macrophages (MΦs), osteoclasts (OCs), and DCs. CD34+c-Kit+Flt3+ cells from BM of MS-RO+ LCH patients produced Langerhans cell (LC)-like cells in vitro. Both LC-like and DC offspring from this progenitor carried the BRAF mutation, confirming their common origin. In both high- and low-risk LCH patients, CD34+c-Kit+Flt3+ progenitor frequency in blood was higher than in healthy donors. In one MS-RO+ LCH patient, CD34+c-Kit+Flt3+ cell frequency in blood and its BRAF-mutated offspring reported response to chemotherapy. CD34+c-Kit+Flt3+ progenitors from blood of both high- and low-risk LCH patients gave rise to DCs and LC-like cells in vitro, but the driver mutation was not easily detectable, likely due to low frequency of mutated progenitors. Mutant BRAF alleles were found in Mo's /MΦs, DCs, LC-like cells, and/or OC-like cells in lesions and/or Mo and DCs in blood of multiple low-risk patients. We therefore hypothesize that in both high- and low-risk LCH, the driver mutation is present in a BM-resident myeloid progenitor that can be mobilized to the blood.
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http://dx.doi.org/10.1182/blood.2020005209DOI Listing
November 2020

A Microchannel-Confined Crystallization Strategy Enables Blade Coating of Perovskite Single Crystal Arrays for Device Integration.

Adv Mater 2020 Apr 4;32(16):e1908340. Epub 2020 Mar 4.

Institute of Functional Nano & Soft Materials (FUNSOM), Jiangsu Key Laboratory for Carbon-Based Functional Materials & Devices, Soochow University, Suzhou, Jiangsu, 215123, P. R. China.

Perovskite single crystals (PSCs) possess superior optoelectronic properties compared to their corresponding polycrystalline films, but their applications of PSCs in high-performance, integrated devices are hindered by their heavy thickness and difficulty in scalable deposition. Here, a microchannel-confined crystallization (MCC) strategy to grow uniform and large-area PSC arrays for integrated device applications is reported. Benefiting from the confinement effect of the microchannels, solution flow dynamics is well controlled, and thus uniform deposition of PSC arrays with suitable thickness is achieved, meaning they are applicable for scale-up device applications. The resulting PSCs possess excellent optoelectronic properties in terms of a long carrier lifetime (175 ns) and an ultralow defect density (2 × 10 cm ), which are comparable to the corresponding bulk crystals. The unique embedded structure of PSCs within the microchannels allows the construction of a high-integration image sensor. This work paves the way toward high-throughput growth of PSCs for integrated optoelectronic devices.
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http://dx.doi.org/10.1002/adma.201908340DOI Listing
April 2020

Hydrothermal synthesis of nitrogen and copper co-doped carbon dots with intrinsic peroxidase-like activity for colorimetric discrimination of phenylenediamine isomers.

Mikrochim Acta 2019 04 15;186(5):288. Epub 2019 Apr 15.

State Key Laboratory of Marine Environmental Science, Xiamen University, Xiamen, 361005, China.

Carbon dots doped with nitrogen and copper have been synthesized via a hydrothermal method. They possess favorable peroxidase-like catalytic activity over a wide range of pH values and temperatures. Specifically, they were used to catalyze the oxidation of ortho- and para-phenylenediamine (OPD and PPD) by HO. The resulting products possess different colors (yellow for OPD and brown for PPD), which can be visually discriminated. The corresponding typical absorption peaks of oxidized products for OPD and PPD are at 413 nm and 500 nm, respectively. The method displays excellent discrimination ability and selectivity over potential interferents. The detection limits are 1.1 μM for OPD and 1.9 μM for PPD. The respective linear ranges are from 5 to 200 μM for OPD and from 2.5 to 700 μM for PPD. The method was applied to the quantification of OPD and PPD in spiked natural waters. Graphical abstract Schematic presentation of the synthesis of nitrogen and copper co-doped carbon dots (N,Cu-CDs) and their application as an enzyme mimic for colorimetric discrimination of ortho-, meta- and para-phenylenediamine (OPD, MPD and PPD).
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http://dx.doi.org/10.1007/s00604-019-3404-yDOI Listing
April 2019

Ratiometric fluorescence detection of riboflavin based on fluorescence resonance energy transfer from nitrogen and phosphorus co-doped carbon dots to riboflavin.

Anal Bioanal Chem 2019 May 27;411(13):2803-2808. Epub 2019 Mar 27.

Department of Applied Chemistry, College of Life Sciences, Fujian Agriculture and Forestry University, Fuzhou, 350002, Fujian, China.

Fluorescent nitrogen and phosphorus co-doped carbon dots (NPCDs) were prepared via a hydrothermal method with citric acid and O-phosphorylethanolamine as precursors. The overlap between the absorption spectrum of riboflavin and the fluorescence emission spectrum of the NPCDs and the relative proximity of the NPCDs to riboflavin due to hydrogen bonding facilitated the formation of a NPCDs/riboflavin fluorescence resonance energy transfer (FRET) system. Thus, a ratiometric fluorescence method for the detection of riboflavin based on the formation of this NPCDs/riboflavin FRET system was developed. The method displayed a sensitive and selective response to riboflavin in the range 0.5-50 μmol/L with a detection limit of 0.17 μmol/L. It was also found to be suitable for the detection of riboflavin in milk and riboflavin pharmaceutical tablets. Graphical abstract Illustration of the preparation of NPCDs and the ratiometric fluorescence detection of riboflavin using the NPCDs/riboflavin FRET system.
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http://dx.doi.org/10.1007/s00216-019-01725-1DOI Listing
May 2019

Hydrothermal synthesis of carbon dots codoped with nitrogen and phosphorus as a turn-on fluorescent probe for cadmium(II).

Mikrochim Acta 2019 02 2;186(3):147. Epub 2019 Feb 2.

Department of Bioinformatics, College of Life Sciences, Fujian Agriculture and Forestry University, Fuzhou, 350002, China.

Nitrogen and phosphorus co-doped carbon dots (N,P-CDs) have been synthesized via hydrothermal method starting from o-phosphorylethanolamine and citric acid. The blue-green fluorescence of the N,P-CDs (with excitation/emission peaks at 325/435 nm) is gradually enhanced on sequential addition of Cd(II) ions. This fluorometric assay works in the 0.5 μM to 12.5 μM Cd(II) concentration range and has a 0.16 μM detection limit. The phenomenon may be attributed to chelation enhanced fluorescence that is induced by the formation of Cd(II)-N,P-CDs complex with functional groups present on the surface. The method has applied to the detection of Cd(II) in spiked serum and urine samples and gave satisfying results. Graphical abstract Schematic presentation of the synthesis of nitrogen and phosphorus co-doped carbon dots (N,P-CDs) and their application as a turn-on fluorescence probe for Cd(II) detection.
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http://dx.doi.org/10.1007/s00604-019-3264-5DOI Listing
February 2019

Macrophages and osteoclasts stem from a bipotent progenitor downstream of a macrophage/osteoclast/dendritic cell progenitor.

Blood Adv 2017 Oct 13;1(23):1993-2006. Epub 2017 Oct 13.

Division of Immunology and.

Monocytes/macrophages (MΦs), osteoclasts (OCs), and dendritic cells (DCs) are closely related cell types of high clinical significance, but the exact steps in their lineage commitment are unclear. In studies on MΦ and DC development, OC development is generally not addressed. Furthermore, findings on DC development are confusing, because monocytes can also differentiate into DC-like cells. To resolve these issues, we have examined the development of monocytes/MΦs, OCs, and DCs from common progenitors, using the homeostatic driver cytokines macrophage colony-stimulating factor, RANK ligand (L), and Flt3L. In mouse bone marrow, B220CD11bc-Kitc-Fms cells could be dissected into a CD27Flt3 population that proved oligopotent for MΦ/OC/DC development (MODP) and a CD27Flt3 population that proved bipotent for MΦ/OC development (MOP). Developmental potential and relationship of MODP and downstream MOP populations are demonstrated by differentiation cultures, functional analysis of MΦ/OC/DC offspring, and genome-wide messenger RNA expression analysis. A common DC progenitor (CDP) has been described as committed to plasmacytoid and conventional DC development. However, the human CDP proved identical to the MODP population, whereas the mouse CDP largely overlapped with the MODP population and was accordingly oligopotent for MΦ, OC, and DC development. The CXCR1 MΦ/DC progenitor (MDP) population described in the mouse generated MΦs and OCs but not DCs. Thus, monocytes/MΦs, OCs, and DCs share a common progenitor that gives rise to a bipotent MΦ/OC progenitor, but a dedicated DC progenitor is currently undefined. The definition of these progenitor populations may serve diagnostics and interventions in diseases with pathogenic activity of MΦs, OCs, or DCs.
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http://dx.doi.org/10.1182/bloodadvances.2017008540DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5728283PMC
October 2017

CD4 T Cell Help Confers a Cytotoxic T Cell Effector Program Including Coinhibitory Receptor Downregulation and Increased Tissue Invasiveness.

Immunity 2017 11 7;47(5):848-861.e5. Epub 2017 Nov 7.

Division of Tumor Biology and Immunology, the Netherlands Cancer Institute-Antoni van Leeuwenhoek, 1066 CX Amsterdam, the Netherlands. Electronic address:

CD4 T cells optimize the cytotoxic T cell (CTL) response in magnitude and quality, by unknown molecular mechanisms. We here present the transcriptomic changes in CTLs resulting from CD4 T cell help after anti-cancer vaccination or virus infection. The gene expression signatures revealed that CD4 T cell help during priming optimized CTLs in expression of cytotoxic effector molecules and many other functions that ensured efficacy of CTLs throughout their life cycle. Key features included downregulation of PD-1 and other coinhibitory receptors that impede CTL activity, and increased motility and migration capacities. "Helped" CTLs acquired chemokine receptors that helped them reach their tumor target tissue and metalloprotease activity that enabled them to invade into tumor tissue. A very large part of the "help" program was instilled in CD8 T cells via CD27 costimulation. The help program thus enhances specific CTL effector functions in response to vaccination or a virus infection.
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http://dx.doi.org/10.1016/j.immuni.2017.10.009DOI Listing
November 2017

Identification of CMTM6 and CMTM4 as PD-L1 protein regulators.

Nature 2017 09 16;549(7670):106-110. Epub 2017 Aug 16.

Division of Molecular Oncology &Immunology, The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands.

The clinical benefit for patients with diverse types of metastatic cancers that has been observed upon blockade of the interaction between PD-1 and PD-L1 has highlighted the importance of this inhibitory axis in the suppression of tumour-specific T-cell responses. Notwithstanding the key role of PD-L1 expression by cells within the tumour micro-environment, our understanding of the regulation of the PD-L1 protein is limited. Here we identify, using a haploid genetic screen, CMTM6, a type-3 transmembrane protein of previously unknown function, as a regulator of the PD-L1 protein. Interference with CMTM6 expression results in impaired PD-L1 protein expression in all human tumour cell types tested and in primary human dendritic cells. Furthermore, through both a haploid genetic modifier screen in CMTM6-deficient cells and genetic complementation experiments, we demonstrate that this function is shared by its closest family member, CMTM4, but not by any of the other CMTM members tested. Notably, CMTM6 increases the PD-L1 protein pool without affecting PD-L1 (also known as CD274) transcription levels. Rather, we demonstrate that CMTM6 is present at the cell surface, associates with the PD-L1 protein, reduces its ubiquitination and increases PD-L1 protein half-life. Consistent with its role in PD-L1 protein regulation, CMTM6 enhances the ability of PD-L1-expressing tumour cells to inhibit T cells. Collectively, our data reveal that PD-L1 relies on CMTM6/4 to efficiently carry out its inhibitory function, and suggest potential new avenues to block this pathway.
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http://dx.doi.org/10.1038/nature23669DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6333292PMC
September 2017

Facile Growth of High-Yield Gold Nanobipyramids Induced by Chloroplatinic Acid for High Refractive Index Sensing Properties.

Sci Rep 2016 11 14;6:36706. Epub 2016 Nov 14.

College of Chemistry and Materials Science, The Key Laboratory of Functional Molecular Solids, Ministry of Education, Anhui Laboratory of Molecular-Based Materials, Anhui Normal University, Wuhu in Anhui Province 241000 China.

Au nanobipyramids (NBPs) have attracted great attention because of their unique localized surface plasmon resonance properties. However, the current growth methods always have low yield or suffer tedious process. Developing new ways to direct synthesis of high-yield Au NBPs using common agents is therefore desirable. Here, we employed chloroplatinic acid as the key shape-directing agent for the first time to grow Au NBPs using a modified seed-mediated method at room temperature. HPtCl was added both during the seed preparation and in growth solution. Metallic Pt, reduced from chloroplatinic acid, will deposit on the surface of the seed nanoparticles and the Au nanocrystals and thus plays a critical role for the formation of Au NBPs. Additionally, the reductant, precursor, and surfactant are all cheap and commonly used. Furthermore, the Au NBPs offer narrow size distribution, two sharp tips, and a shared basis. Au NBPs therefore show much higher refractive index sensitivities than that of the Au nanorods. The refractive index sensitivities and lager figure of merit values of Au NBPs exhibit an increase of 63% and 321% respectively compared to the corresponding values of Au nanorod sample.
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http://dx.doi.org/10.1038/srep36706DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5107934PMC
November 2016

CD27 Agonism Plus PD-1 Blockade Recapitulates CD4+ T-cell Help in Therapeutic Anticancer Vaccination.

Cancer Res 2016 05 28;76(10):2921-31. Epub 2016 Mar 28.

Division of Immunology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek, Amsterdam, the Netherlands.

While showing promise, vaccination strategies to treat cancer require further optimization. Likely barriers to efficacy involve cancer-associated immunosuppression and peripheral tolerance, which limit the generation of effective vaccine-specific cytotoxic T lymphocytes (CTL). Because CD4(+) T cells improve CTL responsiveness, next-generation vaccines include helper epitopes. Here, we demonstrate in mice how CD4(+) T-cell help optimizes the CTL response to a clinically relevant DNA vaccine engineered to combat human papillomavirus-expressing tumors. Inclusion of tumor-unrelated helper epitopes greatly increased CTL priming, effector, and memory T-cell programming. CD4(+) T-cell help optimized the CTL response in all these aspects via CD27/CD70 costimulation. Notably, administration of an agonistic CD27 antibody could largely replace helper epitopes in promoting primary and memory CTL responses, acting directly on CD8(+) T cells. CD27 agonism improved efficacy of the vaccine without helper epitopes, more so than combined PD-1 and CTLA-4 blockade. Combining CD27 agonism with CTLA-4 blockade improved vaccine-induced CTL priming and tumor infiltration, but only combination with PD-1 blockade was effective at eradicating tumors, thereby fully recapitulating the effect of CD4(+) T-cell help on vaccine efficacy. PD-1 blockade alone did not affect CTL priming or tumor infiltration, so these results implied that it cooperated with CD4(+) T-cell help by alleviating immune suppression against CTL in the tumor. Helper epitope inclusion or CD27 agonism did not stimulate regulatory T cells, and vaccine efficacy was also improved by CD27 agonism in the presence of CD4(+) T-cell help. Our findings provide a preclinical rationale to apply CD27 agonist antibodies, either alone or combined with PD-1 blockade, to improve the therapeutic efficacy of cancer vaccines and immunotherapy generally. Cancer Res; 76(10); 2921-31. ©2016 AACR.
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http://dx.doi.org/10.1158/0008-5472.CAN-15-3130DOI Listing
May 2016

Identification of the Common Origins of Osteoclasts, Macrophages, and Dendritic Cells in Human Hematopoiesis.

Stem Cell Reports 2015 Jun 21;4(6):984-94. Epub 2015 May 21.

Division of Immunology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek, Amsterdam 1066 CX, the Netherlands. Electronic address:

Osteoclasts (OCs) originate from the myeloid cell lineage, but the successive steps in their lineage commitment are ill-defined, especially in humans. To clarify OC origin, we sorted cell populations from pediatric bone marrow (BM) by flow cytometry and assessed their differentiation potential in vitro. Within the CD11b(-)CD34(+)c-KIT(+) BM cell population, OC-differentiation potential was restricted to FLT3(+) cells and enriched in an IL3 receptor (R)α(high) subset that constituted less than 0.5% of total BM. These IL3Rα(high) cells also generated macrophages (MΦs) and dendritic cells (DCs) but lacked granulocyte (GR)-differentiation potential, as demonstrated at the clonal level. The IL3Rα(low) subset was re-defined as common progenitor of GR, MΦ, OC, and DC (GMODP) and gave rise to the IL3Rα(high) subset that was identified as common progenitor of MΦ, OC, and DC (MODP). Unbiased transcriptome analysis of CD11b(-)CD34(+)c-KIT(+)FLT3(+) IL3Rα(low) and IL3Rα(high) subsets corroborated our definitions of the GMODP and MODP and their developmental relationship.
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http://dx.doi.org/10.1016/j.stemcr.2015.04.012DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4471835PMC
June 2015

CD8+ T cells produce the chemokine CXCL10 in response to CD27/CD70 costimulation to promote generation of the CD8+ effector T cell pool.

J Immunol 2013 Sep 12;191(6):3025-36. Epub 2013 Aug 12.

Division of Immunology, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.

Various cell types can produce the chemokine CXCL10 in response to IFN-γ stimulation. CXCL10 is generally viewed as a proinflammatory chemokine that promotes recruitment of CD8÷ and Th1-type CD4÷ effector T cells to infected or inflamed nonlymphoid tissues. We show that CXCL10 plays a role during CD8÷ T cell priming in the mouse. Genome-wide expression profiling revealed the Cxcl10 gene as a target of CD27/CD70 costimulation in newly activated CD8÷ T cells. CD27/CD70 costimulation is known to promote activated T cell survival, but CXCL10 did not affect survival or proliferation of primed CD8÷ T cells in vitro. Accordingly, CXCL10 could not fully rescue CD27 deficiency in mice infected with influenza virus. Rather, CXCL10 acted as chemoattractant for other activated CD8⁺ T cells. It signaled downstream of CD27 in a paracrine fashion to promote generation of the CD8÷ effector T cell pool in the Ag-draining lymph nodes. Consistently, CD8÷ T cells required expression of the CXCL10 receptor CXCR3 for their clonal expansion in a CD27/CD70-dependent peptide-immunization model. Our findings indicate that CXCL10, produced by primed CD8÷ T cells in response to CD27/CD70 costimulation, signals to other primed CD8⁺ T cells in the lymph node microenvironment to facilitate their participation in the CD8÷ effector T cell pool.
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http://dx.doi.org/10.4049/jimmunol.1202222DOI Listing
September 2013

Potent monoclonal antibodies against Clostridium difficile toxin A elicited by DNA immunization.

Hum Vaccin Immunother 2013 Oct 12;9(10):2157-64. Epub 2013 Jul 12.

China-US Vaccine Research Center; The First Affiliated Hospital of Nanjing Medical University; Nanjing, P.R. China; Department of Medicine; University of Massachusetts Medical School; Worcester, MA USA.

Recent studies have demonstrated that DNA immunization is effective in eliciting antigen-specific antibody responses against a wide range of infectious disease targets. The polyclonal antibodies elicited by DNA vaccination exhibit high sensitivity to conformational epitopes and high avidity. However, there have been limited reports in literature on the production of monoclonal antibodies (mAb) by DNA immunization. Here, by using Clostridium difficile (C. diff) toxin A as a model antigen, we demonstrated that DNA immunization was effective in producing a panel of mAb that are protective against toxin A challenge and can also be used as sensitive reagents to detect toxin A from various testing samples. The immunoglobulin (Ig) gene usage for such mAb was also investigated. Further studies should be conducted to fully establish DNA immunization as a unique platform to produce mAb in various hosts.
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http://dx.doi.org/10.4161/hv.25656DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3906400PMC
October 2013

Osteoclast precursors in murine bone marrow express CD27 and are impeded in osteoclast development by CD70 on activated immune cells.

Proc Natl Acad Sci U S A 2013 Jul 5;110(30):12385-90. Epub 2013 Jul 5.

Division of Immunology, The Netherlands Cancer Institute, 1066 CX, Amsterdam, The Netherlands.

Osteoclasts (OCs) are bone-resorbing cells that are formed from hematopoietic precursors. OCs ordinarily maintain bone homeostasis, but they can also cause major pathology in autoimmune and inflammatory diseases. Under homeostatic conditions, receptor activator of nuclear factor kappa-B (RANK) ligand on osteoblasts drives OC differentiation by interaction with its receptor RANK on OC precursors. During chronic immune activation, RANK ligand on activated immune cells likewise drives pathogenic OC differentiation. We here report that the related TNF family member CD70 and its receptor CD27 can also mediate cross-talk between immune cells and OC precursors. We identified CD27 on a rare population (0.3%) of B220(-)c-Kit(+)CD115(+)CD11b(low) cells in the mouse bone marrow (BM) that are highly enriched for osteoclastogenic potential. We dissected this population into CD27(high) common precursors of OC, dendritic cells (DCs) and macrophages and CD27(low/neg) downstream precursors that could differentiate into OC and macrophages, but not DC. In a recombinant mouse model of chronic immune activation, sustained CD27/CD70 interactions caused an accumulation of OC precursors and a reduction in OC activity. These events were due to a CD27/CD70-dependent inhibition of OC differentiation from the OC precursors by BM-infiltrating, CD70(+)-activated immune cells. DC numbers in BM and spleen were increased, suggesting a skewing of the OC precursors toward DC differentiation. The impediment in OC differentiation culminated in a high trabecular bone mass pathology. Mice additionally presented anemia, leukopenia, and splenomegaly. Thus, under conditions of constitutive CD70 expression reflecting chronic immune activation, the CD27/CD70 system inhibits OC differentiation and favors DC differentiation.
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http://dx.doi.org/10.1073/pnas.1216082110DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3725107PMC
July 2013

Epithelial and dendritic cells in the thymic medulla promote CD4+Foxp3+ regulatory T cell development via the CD27-CD70 pathway.

J Exp Med 2013 Apr 1;210(4):715-28. Epub 2013 Apr 1.

Division of Immunology and 2 Division of Biological Stress Responses, The Netherlands Cancer Institute, 1066 CX Amsterdam, Netherlands.

CD4(+)Foxp3(+) regulatory T cells (Treg cells) are largely autoreactive yet escape clonal deletion in the thymus. We demonstrate here that CD27-CD70 co-stimulation in the thymus rescues developing Treg cells from apoptosis and thereby promotes Treg cell generation. Genetic ablation of CD27 or its ligand CD70 reduced Treg cell numbers in the thymus and peripheral lymphoid organs, whereas it did not alter conventional CD4(+)Foxp3(-) T cell numbers. The CD27-CD70 pathway was not required for pre-Treg cell generation, Foxp3 induction, or mature Treg cell function. Rather, CD27 signaling enhanced positive selection of Treg cells within the thymus in a cell-intrinsic manner. CD27 signals promoted the survival of thymic Treg cells by inhibiting the mitochondrial apoptosis pathway. CD70 was expressed on Aire(-) and Aire(+) medullary thymic epithelial cells (mTECs) and on dendritic cells (DCs) in the thymic medulla. CD70 on both mTECs and DCs contributed to Treg cell development as shown in BM chimera experiments with CD70-deficient mice. In vitro experiments indicated that CD70 on the CD8α(+) subset of thymic DCs promoted Treg cell development. Our data suggest that mTECs and DCs form dedicated niches in the thymic medulla, in which CD27-CD70 co-stimulation rescues developing Treg cells from apoptosis, subsequent to Foxp3 induction by TCR and CD28 signals.
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http://dx.doi.org/10.1084/jem.20112061DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3620350PMC
April 2013

The CD27 and CD70 costimulatory pathway inhibits effector function of T helper 17 cells and attenuates associated autoimmunity.

Immunity 2013 Jan 15;38(1):53-65. Epub 2012 Nov 15.

Division of Immunology, The Netherlands Cancer Institute-Antoni van Leeuwenhoek, 1066 CX Amsterdam, The Netherlands.

T helper 17 (Th17) cells protect against infection but also promote inflammation and autoimmunity. Therefore, the factors that govern Th17 cell differentiation are of special interest. The CD27 and CD70 costimulatory pathway impeded Th17 effector cell differentiation and associated autoimmunity in a mouse model of multiple sclerosis. CD27 or CD70 deficiency exacerbated disease, whereas constitutive CD27 signaling strongly reduced disease incidence and severity. CD27 signaling did not impact master regulators of T helper cell lineage commitment but selectively repressed transcription of the key effector molecules interleukin-17 (IL-17) and the chemokine receptor CCR6 in differentiating Th17 cells. CD27 mediated this repression at least in part via the c-Jun N-terminal kinase (JNK) pathway that restrained IL-17 and CCR6 expression in differentiating Th17 cells. CD27 signaling also resulted in epigenetic silencing of the Il17a gene. Thus, CD27 costimulation via JNK signaling, transcriptional, and epigenetic effects suppresses Th17 effector cell function and associated pathological consequences.
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http://dx.doi.org/10.1016/j.immuni.2012.09.009DOI Listing
January 2013

Protective antibody responses against Clostridium difficile elicited by a DNA vaccine expressing the enzymatic domain of toxin B.

Hum Vaccin Immunother 2013 Jan 10;9(1):63-73. Epub 2012 Nov 10.

Jiangsu Province Key Laboratory in Infectious Diseases, The First Affiliated Hospital of Nanjing Medical University; Nanjing, China.

A DNA vaccination approach was used in the current study to screen for the immunogenicity of different fragments of toxin A and toxin B from Clostridium difficile. With this approach, protein antigens do not need to be produced in vitro and the immunogenicity of candidate C. difficile antigens can be identified directly in animals. Codon optimized toxin gene fragments were individually cloned into the DNA vaccine vector and tested in mice and rabbits for their ability to elicit C. difficile toxin-specific antibody responses. Only a subset of the C. difficile toxin fragments, including the C-terminal receptor binding domain of toxin A and a novel N-terminal enzymatic domain of toxin B, were able to elicit protective antibody responses as determined by protection of target cells in a cytotoxicity assay or by preventing death of mice in a passive antibody protection study. Significantly, antibodies elicited by the novel N-terminus of the toxin B DNA vaccine were able to increase the level of protection when used in combination with anti-toxin A antibodies in a toxin challenge model in mice.
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http://dx.doi.org/10.4161/hv.22434DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3667947PMC
January 2013

The Pim kinase pathway contributes to survival signaling in primed CD8+ T cells upon CD27 costimulation.

J Immunol 2010 Dec 3;185(11):6670-8. Epub 2010 Nov 3.

Division of Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.

Stimulation of the costimulatory receptor CD27 by its ligand CD70 has proved important for the generation of primary and memory CD8(+) T cell responses in various models of antigenic challenge. CD27/CD70-mediated costimulation promotes the survival of primed T cells and thereby increases the size of effector and memory populations. In this paper, we reveal molecular mechanisms underlying the prosurvival effect of CD27. CD27 signaling upregulated expression of the antiapoptotic Bcl-2 family member Bcl-x(L). However, genetic reconstitution of Cd27(-/-) CD8(+) T cells with Bcl-x(L) alone or in combination with the related protein Mcl-1 did not compensate for CD27 deficiency in the response to influenza virus infection. This suggested that CD27 supports generation of the CD8(+) effector T cell pool not only by counteracting apoptosis via Bcl-2 family members. Genome-wide mRNA expression profiling indicated that CD27 directs expression of the Pim1 gene. Pim-1 is a serine/threonine kinase that sustains survival of rapidly proliferating cells by antiapoptotic and prometabolic effects that are independent of the mammalian target of rapamycin (mTOR) pathway. In TCR-primed CD8(+) T cells, CD27 could increment Pim-1 protein expression and promote cell survival throughout clonal expansion independent of the mTOR and IL-2R pathways. In addition, introduction of the Pim1 gene in Cd27(-/-) CD8(+) T cells partially corrected their defect in clonal expansion and formation of an effector pool. We conclude that CD27 may contribute to the survival of primed CD8(+) T cells by the upregulation of antiapoptotic Bcl-2 family members but also calls the Pim-1 kinase survival pathway into action.
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http://dx.doi.org/10.4049/jimmunol.1000159DOI Listing
December 2010

Dexamethasone treatment during the expansion phase maintains stemness of bone marrow mesenchymal stem cells.

J Tissue Eng Regen Med 2010 Jul;4(5):374-86

R&D Division, Progentix BV, Bilthoven, The Netherlands.

Human mesenchymal stem cells (hMSCs) can form various mesodermal tissues when grown under appropriate conditions. Dexamethasone (Dex) is regularly used to stimulate the osteogenic potential of hMSCs and it has recently been reported to increase the cell expansion rate. In this study we have investigated the effect of low-dose Dex treatment (10(-8) M) on the multipotency of expanded hMSCs, using histological, biochemical and molecular biological techniques. Early passage (P2-3) and late passage (P6) cells were positive (>90%) for mesenchymal adhesion cell markers (CD105/CD29/CD44/CD166/CD90) and negative (<10%) for haematopoietic markers (CD34/CD45/CD14). Dex did not change the overall expression pattern of these cell surface markers. Expanded hMSCs gave rise to specialized cell lineages when grown in differentiation-promoting medium. Depending on the donor, Dex treatment improved the potency for osteogenic, adipogenic and chondrogenic differentiation of expanded hMSCs. Dex also prevented the loss of proliferative potential of hMSCs upon sequential passaging and the loss of the typical hMSCs surface phenotype. hMSCs gene expression analysis showed that low-dose Dex negatively regulated transcription of genes correlated with apoptosis and differentiation, and positively regulated genes associated with cell proliferation. In conclusion, the collective data argue that low-dose Dex preserves the stemness of hMSCs during repeated passaging, as indicated by the maintenance of the stem cell phenotype, proliferative capacity and multi-lineage differentiation potential.
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http://dx.doi.org/10.1002/term.250DOI Listing
July 2010

CD27 sustains survival of CTLs in virus-infected nonlymphoid tissue in mice by inducing autocrine IL-2 production.

J Clin Invest 2010 Jan 1;120(1):168-78. Epub 2009 Dec 1.

Division of Immunology, The Netherlands Cancer Institute, Plesmanlaan 121, Amsterdam, The Netherlands.

Immunity to infections relies on clonal expansion of CD8+ T cells, their maintenance as effector CTLs, and their selection into a memory population. These processes rely on delivery of survival signals to activated CD8+ T cells. We here reveal the mechanism by which costimulatory CD27-CD70 interactions sustain survival of CD8+ effector T cells in infected tissue. By unbiased genome-wide gene expression analysis, we identified the Il2 gene as the most prominent CD27 target gene in murine CD8+ T cells. In vitro, CD27 directed IL-2 expression and promoted clonal expansion of primed CD8+ T cells exclusively by IL-2-dependent survival signaling. In mice intranasally infected with influenza virus, Cd27-/- CD8+ effector T cells displayed reduced IL-2 production, accompanied by impaired accumulation in lymphoid organs and in the lungs, which constitute the tissue effector site. Reconstitution of Cd27-/- CD8+ T cells with the IL2 gene restored their accumulation to wild-type levels in the lungs, but it did not rescue their accumulation in lymphoid organs. Competition experiments showed that the IL-2 produced under the control of CD27 supported effector CD8+ T cell survival in the lungs in an autocrine manner. We conclude that CD27 signaling directs the IL-2 production that is reportedly essential to sustain survival of virus-specific CTLs in nonlymphoid tissue.
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http://dx.doi.org/10.1172/JCI40178DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2798690PMC
January 2010

Mice deficient for CD137 ligand are predisposed to develop germinal center-derived B-cell lymphoma.

Blood 2009 Sep 16;114(11):2280-9. Epub 2009 Jul 16.

Division of Immunology, The Netherlands Cancer Institute, Amsterdam, The Netherlands.

In the germinal center (GC), B cells proliferate dramatically and diversify their immunoglobulin genes, which increases the risk of malignant transformation. The GC B-cell reaction relies on crosstalk with follicular dendritic cells (FDCs), to which the costimulatory receptor CD137 on FDCs and its ligand on GC B cells potentially contribute. We report that mice deficient for CD137 ligand (CD137L) are predisposed to develop B-cell lymphoma, with an incidence of approximately 60% at 12 months of age. Lymphoma membrane markers were characteristic of GC B cells. Longitudinal histologic analysis identified the GC as site of oncogenic transformation and classified 85% of the malignancies found in approximately 200 mice as GC-derived B-cell lymphoma. To delineate the mechanism underlying lymphomagenesis, gene expression profiles of wild-type and CD137L-deficient GC B cells were compared. CD137L deficiency was associated with enhanced expression of a limited gene set that included Bcl-10 and the GC response regulators Bcl-6, Spi-B, Elf-1, Bach2, and activation-induced cytidine deaminase. Among these are proto-oncogenes that mediate GC B-cell lymphoma development in humans. We conclude that CD137L ordinarily regulates the GC B-cell response and thereby acts as a tumor suppressor.
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http://dx.doi.org/10.1182/blood-2009-03-208215DOI Listing
September 2009

Costimulatory ligand CD70 allows induction of CD8+ T-cell immunity by immature dendritic cells in a vaccination setting.

Blood 2009 May 11;113(21):5167-75. Epub 2009 Mar 11.

The Netherlands Cancer Institute, Amsterdam, The Netherlands.

The use of dendritic cells (DCs) as anticancer vaccines holds promise for therapy but requires optimization. We have explored the potential of costimulatory ligand CD70 to boost the capacity of DCs to evoke effective CD8(+) T-cell immunity. We show that immature conventional DCs, when endowed with CD70 expression by transgenesis, are converted from a tolerogenic state into an immunogenic state. Adoptively transferred CD70-expressing immature DCs could prime CD8(+) T cells, by CD27, to become tumor-eradicating cytolytic effectors and memory cells with a capacity for robust secondary expansion. The CD8(+) T-cell response, including memory programming, was independent of CD4(+) T-cell help, because the transferred immature DCs were loaded with major histocompatibility complex class I-restricted peptide only. Without CD70 expression, the DCs generated abortive clonal expansion, dysfunctional antitumor responses, and no CD8(+) T-cell memory. CD70-expressing CD8(+) DCs were the primary subset responsible for CD8(+) T-cell priming and performed comparably to fully matured DCs. These data highlight the importance of CD27/CD70 interactions at the T-cell/DC interface and indicate that CD70 should be considered in the design of DC vaccination strategies.
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http://dx.doi.org/10.1182/blood-2008-03-148007DOI Listing
May 2009

Expression of costimulatory ligand CD70 on steady-state dendritic cells breaks CD8+ T cell tolerance and permits effective immunity.

Immunity 2008 Dec 8;29(6):934-46. Epub 2008 Dec 8.

Division of Immunology, The Netherlands Cancer Institute, 1066 CX Amsterdam, The Netherlands.

Steady-state dendritic cells (DCs) maintain peripheral T cell tolerance, whereas mature DCs generate immunity. CD70 is a costimulatory ligand acquired upon DC maturation. To determine its impact on T cell fate, we have generated mice that constitutively express CD70 in conventional DCs (cDCs). In these mice, naive CD4+ and CD8+ T cells spontaneously convert into effector cells. Administration of peptide without adjuvant, which is ordinarily tolerogenic, elicited tumor-eradicating CD8+ T cell responses and robust CD4+ T cell-independent memory. CD70 was also constitutively expressed in cDCs that inducibly present viral epitopes. In this case, tolerance induction was prevented as well. The antigen-presenting DCs generated protective immunity to virus infection and broke a pre-existing state of CD8+ T cell tolerance. Thus, the sole expression of CD70 by otherwise immature cDCs sufficed to convert CD8+ T cell tolerance into immunity, defining the importance of CD27-CD70 interactions at the interface between T cell and DC.
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http://dx.doi.org/10.1016/j.immuni.2008.10.009DOI Listing
December 2008
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