bluuebunny/crossref_metadata_2025_split huggingface dataset:
Analyzing the in vivo contribution of G-protein coupled receptors for naive B cell trafficking in lymph nodes (44.23)
Authors: Stein Jens , Coelho Fernanda , Soriano Silvia , Natale Daniela , Swoger Jim , Mayer Juergen , Chai Qian , Hons Miroslav , Pieczyk Markus , Zerwes Hans-Guenter , Junt Tobias , Sailer Andreas , Ludewig Burkhard , Sharpe James , Figge Marc Thilo 
Published: January 2023

Abstract
B cell motility within lymphoid tissue is precisely orchestrated by G-protein-coupled receptors (GPCRs) of the chemokine receptor family and other GPCRs, including the recently described 7α,25-dihydroxycholesterol receptor Ebi2. Here, we performed an exhaustive twophoton microscopy (2PM) analysis of the contribution of the chemokine receptors CXCR4, CXCR5 and CCR7, as well as Ebi2, during the dynamic migration of naïve B cells inside peripheral lymph nodes (PLNs) and the kinetics of B cell accumulation from the T cell area in B cell follicles. Using the intravital 2PM model of murine popliteal PLNs paired with genetic and pharmacological inhibition of GPCRs and their ligands, we observed a non-redundant role for CXCR5 for dynamic B cell motility in the T cell area and B cell follicles, while the functional absence of CXCR4 and CCR7 did not influence B cell migration parameters. Although CXCR5 was central for efficient B cell accumulation in B cell follicles, we did not find evidence for directed migration of T cell area-borne B cells towards B cell follicles, supporting a chemokinetic, and not chemotactic, role for the CXCR5 ligand CXCL13 during this process. Lack of Ebi2 confined B cells to the central part of B cell follicles, resulting in higher average migration velocities as compared to wild type B cells. In summary, our data provide novel insight into the contribution of GPCRs during the dynamic migration of naïve B cells in non-inflamed and inflamed PLNs.
The role of interleukin (IL)-22 on the proliferation of human keratinocyte cell line, HaCaT by Ultraviolet B (UVB) irradiation (44.27)
Authors: Kim Yejin , Bae Seyeon , Kim Hyemin , Yu Yeonsil , Kim Hang-Rae , Hwang Young-il , Kang Jae Seung , Lee Wang Jae 
Published: January 2023

Abstract
Interleukin 22 (IL-22), a member of IL-10 family, is a potent mediator of inflammatory responses. It is produced by activated CD4+ T cells and natural killer (NK) cells, but its receptor expression is restricted to nonhematopoietic cells in the skin, pancreas, intestine, liver, lung and kidney. IL-22 suppresses IL-4 production from Th2 cells and induces acute phase proteins in liver and pancreas. It is recently found that IL-22 plays a critical role in the maintenance of epidermal homeostasis by controlling cell cycle of keratinocytes. Therefore, we investigated that role of IL-22 on the proliferation of UVB-irradiated human keratinocytes, HaCaT. First, we found the increase of IL-22 mRNA expression was increased in HaCaT by UVB irradiation (150J/m2). When UVB-irradiated HaCaT was cultured in the presence of recombinant IL-22, the suppressed proliferation of HaCaT by UVB was rescued. It was closely related with the progression of cell cycle in UVB-irradiated HaCaT. We confirmed that the hyperproliferation and cell cycle progression of UVB-irradiated HaCaT by the addition of activated T cells or its culture supernatant. Taken together, IL-22 plays a critical role in the deterioration of epidermal hyperplasia by UVB irradiation. And it suggests that UVB-induced skin inflammation could effectively be controlled by the regulation of IL-22 production and its action on keratinocytes.
Visualization of IL-22 in mouse intestinal inflammation with an IL-22 tdTomato reporter mouse Wei Shen1, Wenqing Li1, Lionel Feigenbaum2, Julie A. Hixon1 and Scott K. Durum1. 1 Laboratory of Molecular Immunoregulation, CIP, CCR, NCI. 2 Laboratory Animal Sciences Program, CCR, NCI, Frederick MD. (44.5)
Authors: Shen Wei , Li Wenqing , Feigenbaum Lionel , Hixon Julie , Durum Scott 
Published: January 2023

Abstract
Interleukin (IL) 22 is produced by innate and adaptive immune cells and has activities in host defense, barrier function, tissue repair and inflammation. Previous studies of IL-22-producing cells have relied on ex-vivo restimulation, a method which assays the capability of cells to produce the cytokine, but not the actual production in vivo. To visualize IL-22 producing cells during immune responses in vivo, a bacterial artificial chromosome (BAC) was modified to introduce the fluorescent reporter gene (tdTomato) into the Il-22 locus. In vitro, the tdTomato reporter was visualized in splenic T cells cultured under Th17 conditions, and in cells from lamina propria following stimulation with IL-23. In colitis induced by either DSS or T cell (CD4+CD45RBhigh) transfer, intestinal intraepithelial cells were isolated and showed expression of the IL-22 reporter by quantitative real-time PCR and flow cytometry analysis. Visualized in histological sections, most of the tdTomato-positive cells in these induced models of inflammatory bowel disease were first present in the mesenteric lymph nodes, and then accumulated inside lamina propria of distal small intestine and colon tissues. In conclusion, this novel IL-22 reporter was expressed in the intestine and draining lymph nodes in several colitis models and will be useful in identifying the cell types, their site of commitment and sites of production of this key cytokine in homeostasis and models of infection of intestine and lung.
Interleukin-22 drives endogenous thymic regeneration in mice (44.6)
Authors: Dudakov Jarrod , Hanash Alan , Jenq Robert , Young Lauren , Ghosh Arnab , Singer Natalie , West Mallory , Smith Odette , Holland Amanda , Tsai Jennifer , Boyd Richard , van den Brink Marcel 
Published: January 2023

Abstract
Thymic regeneration is a crucial function that allows for renewal of immune competance after stress, infection or immunodepletion, however the mechanisms governing this rejuvenation remain poorly understood. Here we detail a framework of endogenous thymic regeneration centred on IL-22, a recently identified cytokine primarily implicated in maintenance of epithelial barrier function. Although IL-22 was redundant for steady-state thymopoiesis, thymic recovery was impaired in IL-22-deficient mice and intrathymic levels of IL-22 were significantly increased in WT mice following thymic damage. IL-22, which signalled through thymic epithelial cells and promoted their proliferation and survival, was upregulated by radio-resistant RORγ(t)+NKp46-CCR6+ lymphoid tissue-inducer cells after thymic injury under the control of dendritic cell-derived IL-23 and triggered by the depletion of CD4+CD8+ double positive (DP) thymocytes. Importantly, administration of IL-22 enhanced thymic recovery following irradiation damage. These studies reveal a network of endogenous thymus regeneration where 1) the depletion of DP thymocytes triggers 2) upregulation of IL-23 by DCs that induces 3) the production of IL-22 by thymic LTi. This cascade of events leads to regeneration of the epithelial microenvironment and, ultimately, to rejuvenation of thymopoiesis; presenting an innovative strategy for improving immune competence in patients whose thymus has been damaged from infection or cytoreductive therapy.
Chemokine guidance of central memory T cells is critical for anti-viral recall responses in lymph nodes (44.8)
Authors: Sung Jung Hwan , von Andrian Ulrich 
Published: January 2023

Abstract
A defining feature of vertebrate immunity is the capacity to acquire immunological memory against recurrent pathogens. During a viral infection, virus-specific memory T cells accelerate anti-viral effector responses and promote faster viral clearance than naive T cells (Tn), but the mechanism for this enhanced protection has been unclear. To address this question, mice were subcutaneously injected with either live virus or antigen (Ag)-pulsed dendritic cells (DCs) and the response of Tn and central memory T cells (Tcm) was visualized in draining lymph nodes (LNs). Upon challenge with Ag-pulsed DCs that carried Ag to deep T cell area, Tn and Tcm interacted similarly with Ag-pulsed DCs. Upon viral challenge, however, Tcm relocalized much more efficiently than Tn toward regions of initial viral infection in the medullary, interfollicular and subcapsular area. This redistribution depended upon chemokine receptor CXCR3 and occured in two sequential steps driven by distinct cytokines and chemokines. Initially, type I interferon-induced CXCL10 promoted peripheralization of Tcm independently of Ag specificity. Subsequently, upon encountering cognate Ag, Tcm produced interferon-γ, which in turn induced a second CXCR3 ligand, CXCL9. Upon viral infection, in vivo recall responses by CXCR3-deficient Tcm were markedly compromised, whereas in vitro responses were intact, suggesting that CXCR3-dependent Tcm relocalization is essential for intranodal anti-viral Tcm function.
Inhibition of iNKT cells by adenosine A2A receptor activation in patients with sickle cell disease (45.1)
Authors: Linden Joel , Lin Gene , Neuberg Donna , Nathan David , Field Joshua 
Published: January 2023

Abstract
Invariant natural killer T (iNKT) cells comprise a minor subset of lymphocytes that are activated by CD1d-restricted lipid antigens produced by pathogens or by the host in response to ischemia reperfusion-injury (IRI). Sickle cell disease (SCD) causes IRI due to chronic widely disseminated vaso-occlusion. IRI and SCD cause iNKT cell activation and release of IFN-γ that triggers an inflammatory cascade with recruitment and activation of other leukocytes to propagate tissue inflammation and injury. In mice with SCD, deletion of iNKT cells or inhibition of their activation with anti-CD1d antibodies or adenosine A2A receptor (A2AR) agonists inhibits tissue inflammation and injury at steady state or during evoked disease exacerbations. People with SCD have increased numbers of a subset iNKT cells that express cellular activation markers including activated NFκB (phospho-p65). The activated iNKT cell-subset concordantly displays elevated A2ARs that cause activated iNKT cells to become hypersensitve to inhibition by adenosine. Infusion of very low doses (1.5 nM in blood) of the A2AR agonist regadenoson into SCD patients results in no cardiovascular effects, but a rapid inhibition of iNKT cell NFκB and a reduction in A2AR immunoreactivity. We plan to initiate a clinical trial to determine if regadenoson infusion reduces the severity and duration of vaso-occlusive pain crises or acute chest syndrome in SCD patients.
INF-γ production of NK cells is suppressed in cancer patients. (45.10)
Authors: Lee Hyo Jun , Koh Jiae , Kim Jongsun 
Published: January 2023

Abstract
Natural killer (NK) cells are the innate immune system that play an important role in killing viral infected and transformed cancer cells by direct cell to cell interaction. NK cells also secrete cytokines such as interferon (IFN)-γ and TNF-α which primes subsequent adaptive immune responses. However, tumor cells employ many different strategies to evade NK cells. Moreover, tumor cells secrete molecules to directly inhibit the function of immune cells of both innate and adaptive immunity. Here, we designed to investigate whether NK cells from cancer patients exhibit an altered ability to produce INF-γ. The results showed that peripheral blood mononuclear cells (PBMC) and purified NK cells of the cancer patients had suppressed ability to produce IFN-γ. Therefore, we propose that impaired IFN-γ production in peripheral blood mononuclear cells and in purified NK cells reflects immunosuppression and inadequate antitumor immune response in cancer patients. Thus, the measurement of INF-γ producing ability of NK cells in clinical blood samples may allow to assess the impact of immunosuppression on these effector cells, and this information may be helpful in understanding cancer and pathogenesis.
Human BDCA3+ dendritic cells (mDC2) recognize HCV-infected hepatoma cells and produce IFN-λs (45.14)
Authors: Zhang Shuye , Kodys Karen , Szabo Gyongyi 
Published: January 2023

Abstract
IFN-lambda (IFN-λ) including IL-28a, IL-28b and IL-29 are found closely associated with outcome of HCV-infected patients, however, the mechanism of their induction and cellular sources during HCV-infection are poorly understood. Using co-cultures between normal human peripheral blood mononuclear cells (PBMCs) and JFH-1 HCV virus infected Huh7.5 (HCVcc/Huh7.5) cells, we found that human PBMCs recognized HCVcc/Huh7.5 cells and in response produced all three types of IFNs (IFN-α, IFN-γ and IFN-λ). We determined that a rare dendritic cell (DC) subset, the mDC2 cells (also referred to as CD141+ myeloid DCs), were the major producers of IL-28 and IL-29 in co-cultures with HCVcc/Huh7.5 cells. TLR3 and not TLR7, 8 or 9 stimulation induced IL-28 and IL-29 in mDC2 and endosomal maturation was required for IFN-λ induction by HCVcc/Huh7.5 cells. We further revealed that mDC2 is activated through a cell-cell contact and endocytosis mediated pathway in response to HCVcc/Huh7.5 cells. Finally, we found that IFN-α and IFN-λ production was inter-related as IFN-λ augmented IFN-α production from pDCs and IFN-α significantly increased IFN-λ production. In conclusion, our novel data identifies mDC2 as a major source of IFN-λs in human PBMCs in response to HCV-infected cells and implies that mDC2 is activated through the TLR3 pathway. These observations indicate human DCs can efficiently initiate immune response against HCV infection and highlight the role of IFN-λ in HCV-infection.
Rapid activation and migration of lymph node resident dendritic cells in response to Influenza vaccination. (45.18)
Authors: Woodruff Matthew , Carroll Michael 
Published: January 2023

Abstract
While the existence of lymph node resident dendritic cell (LNDC) populations is widely acknowledged, little is known about their contribution to the generation of an active immune response. Following up on earlier studies describing the importance of LNDCs in humoral immunity, we have interrogated the role of these cells in response to lymph borne antigen. Using UV-inactivated influenza as a model, we have observed direct capture of viral antigen by LNDC populations within 10 minutes of viral injection. Live imaging of viral capture using multi- photon microscopy reveals novel global activation of LNDCs within 60 minutes of viral arrival. Four-dimensional tracking, as well as whole-node fluorescent reconstruction, suggests a mass migration of LNDCs from the T cell cortex into the medullary compartment to areas of high antigen density, likely in response to innate signaling from the node periphery. These data indicate a novel mechanism whereby LNDCs rapidly respond to innate signaling through activation and homing to areas of high antigen density. We believe that this event may represent an early link between innate and adaptive immunity whereby activated DCs within the draining node have access to antigen well prior to the described migration of skin resident DCs from the periphery. We expect that a better understanding of these responses will be highly relevant to both lymph borne diseases, as well as future vaccine development.
T-cell education of dendritic cell responsiveness (45.2)
Authors: Abdi Kaveh 
Published: January 2023

Abstract
LPS-activated Dendritic Cells (DCs) are thought to follow a set program: first secreting inflammatory cytokines (e.g. IL 12p75) and then becoming refractory to further stimulation (i.e. “exhausted”). Here we show that these concepts need to be reconsidered. LPS-activated mouse DCs produce ample IL-12p40, but no p75 without additional stimulating signals from T cells or their products (i.e. IFN-γ, CD40L plus GM-CSF and IL-4). The prevailing view that LPS induces the production of p75 is largely due to the fact that many early studies used detection antibodies that do not distinguish between p40 and p75; or used DC populations containing small numbers of contaminating T cells. Second, although LPS-stimulated DCs do indeed lose their responsiveness to LPS about 24 hours after stimulation, they nevertheless remain perfectly capable of making inflammatory cytokines in response to signals from activated T cells, and to a combination of CD40-L plus soluble T-cell products. In addition, far from being rigidly programmed by the original activating stimulus, the DCs retained sufficient plasticity to respond differentially to interactions with TH0, TH1, TH2 and TH17 T cells, showing that T cells can change the subsequent activity of the DCs with which they interact. These data indicate that DCs are not programmed to respond to stimulation with a pre-determined series of events, but remain sensitive to their environment and can change their differentiation accordingly.
SLC11A1 expression in innate lymphocytes (N)RAMPs up activation (45.5)
Authors: Hedges Jodi , Snyder Deann , Jerome Maria , Holderness Jeff , Jutila Mark 
Published: January 2023

Abstract
SLC11A1 is a divalent ion transporter also known as natural resistance-associated macrophage protein 1 (NRAMP1) and formerly Bcg/Lsh/Ity locus, as mutations to this locus in mice result in susceptibility to Mycobacterium bovis (BCG), Leishmania and Salmonella infections. SLC11A1 was thought to be exclusively expressed in monocyte/macrophages and dendritic cells and to function in cell activation through iron-dependent interference with protein tyrosine phosphatase (PTP) activity. Expression of functional SLC11A1 in vivo has been consistently associated with increased IFNγ expression. We have detected SLC11A1 protein in the majority of γδ T cells, in NK cell subsets and in CD3+CD45RO+ T cells from cattle and humans. SLC11A1+ lymphocytes were more prone to activation and IFNγ expression than were SLC11A1- cells. Chemical blockade of PTPs and iron excess induced lymphocyte activation, underscoring their capacity for activation by PTP inhibition and a potential role for iron, the primary SLC11A1 substrate. MOLT14, a naturally SLC11A1- human γδ TCR+ cell line was transfected to express SLC11A1 which rendered the cells more prone to activation. Commonly used inbred laboratory mouse strains express a non-functional SLC11A1 protein, thus, innate T cell activation may be underestimated in models using these mice. These data support a novel role for SLC11A1 in activation of innate lymphocytes that are important early sources of IFNγ.
Transcription factor Nrf2 (NF-E2 Related Factor 2) enhances myeloid-derived suppressor cell (MDSC) accumulation and tumor progression (46.13)
Authors: Beury Daniel , Nelson Cassandra , Ostrand-Rosenberg Suzanne 
Published: January 2023

Abstract
Previous studies have shown that MDSC block adaptive anti-tumor immunity by producing high levels of oxidizing agents such as reactive oxygen species (ROS), nitric oxide (NO), and peroxynitrite. Despite high levels of the toxic oxidizing agents, MDSC survive and suppress anti-tumor immunity. We hypothesize that MDSC survival is mediated by the antioxidant-regulating transcription factor Nrf2. To test this hypothesis, BALB/c wild type and Nrf2-/- mice were injected with 4T1 mammary carcinoma cells and assayed weekly for percentage of MDSC in the blood and for MDSC levels of ROS and glutathione. Mice were also followed for survival. Nrf2-/- MDSC had more ROS and less glutathione than wild type MDSC, indicating that Nrf2-/- MDSC were more oxidatively stressed. Increased oxidative stress is likely to lead to increased apoptosis of MDSC and reduced immune suppression. Tumor-bearing Nrf2-/- and wild type mice accumulated MDSC in the blood with increasing tumor-burden. However, tumor-bearing Nrf2-/- mice had less MDSC than wild type mice for a given sized primary tumor. Therefore, MDSC either accumulate more slowly or they apoptose more quickly in Nrf2-/- vs. wild type mice. Tumor-bearing Nrf2-/- mice lived longer than wild type mice demonstrating that Nrf2 contributes to tumor progression; consistent with our hypothesis that Nrf2 regulates MDSC survival, resulting in fewer MDSC in Nrf2-/- mice, thereby increasing anti-tumor immunity against metastatic disease.
Hypoxia can suppress T cell activation in a mechanism independent of A2A adenosine receptor (46.27)
Authors: Madasu Manasa Mahathi , Subramanian Meenakshi , Kini Radhika , Ohta Akiko , Sitkovsky Michail , Ohta Akio 
Published: January 2023

Abstract
Tissue hypoxia plays a key role in the establishment of immunosuppressive environment in vivo, most notably in tumors. Hypoxia promotes local increase of extracellular adenosine, and interaction of adenosine with A2A adenosine receptor (A2AR) strongly inhibits immune activation. The adenosine-A2AR pathway may represent a mechanism of the physiological immunoregulation initiated by hypoxia. However, in this study, we found that hypoxia can also exert its T cell inhibitory effects even in the absence of A2AR. When mouse T cells were activated by anti-CD3 mAb, hypoxia (1% oxygen) strongly impaired T cell activation. Hypoxia showed the same degree of inhibition against wild-type and A2AR-deficient T cells suggesting that hypoxia could inhibit T cells in an A2AR-independent mechanism. In comparison to A2AR stimulation, this A2AR-independent pathway strongly inhibited cell proliferation and cytotoxicity, while IFN-γ-producing activity was more susceptible to A2AR stimulation. In contrast to sustained functional impairment in T cells after A2AR stimulation, T cells activated under hypoxia immediately recovered from the immunosuppressed state and produced high levels of IFN-γ upon restimulation. Although previous in vivo studies have shown the A2AR-dependent immunosuppression by hypoxia, the current study suggests the involvement of multiple different mechanisms in T cell inhibition by hypoxia.
Chemotherapeutic drugs trigger rapid apoptotic induction and caspase-1/ inflammasome signaling in murine macrophages (46.33)
Authors: Antonopoulos Christina , Dubyak George 
Published: January 2023

Abstract
The success of certain cancer chemotherapy drugs relies critically on the host immune system. In some cancer models, induction of NLRP3/caspase-1/IL-1β signaling cascades in dendritic cells is required for effective anti-tumor immunity. Recent studies by Sauter et al. (Cancer Biol Ther 2010) reported (and we have confirmed) that the chemotherapeutic anthracycline, doxorubicin (DOX), induces NLRP3 inflammasome-dependent IL-1β secretion from murine macrophages. We have also tested several other chemotherapy drugs for their ability to induce IL-1β secretion and/or apoptotic induction in LPS-primed murine bone marrow-derived macrophages (BMDM). Staurosporine (ST), a pro-apoptotic kinase inhibitor, was identified as another rapid inducer of caspase-1 activation and IL-1β release; ST initially (over the first 3 h) activates a K+ efflux-independent casp-1 activation but secondarily engages a K+ efflux-dependent pathway at later (&gt;3h) treatment times. Both DOX and ST also induce rapid (within 1-4 h) accumulation of casp-3/7 activity which coincides with, or precedes, the casp-1 activation and IL-1β secretion responses. Ongoing studies are testing whether: 1) casp-3/7-mediated cleavage of the pannexin-1 channel contributes to the K+ efflux required for NLRP3 inflammasome activation by DOX; and 2) NLRP3-independent inflammasomes mediate the initial K+ efflux-independent IL-1β release elicited by ST.