bluuebunny/crossref_metadata_2025_split huggingface dataset:
Menopause accelerates immune senescence and diminishes immune response to vaccination (90.8)
Authors: Messaoudi Ilhem , Engelmann Flora , Barron Alexander , Urbanski Henryk , Neuringer Martha 
Published: January 2023

Abstract
Menopause and the associated loss of estrogen and progesterone represent the most dramatic physiological change in aging women. Aging is accompanied by a decline in immunity referred to as immune senescence that significantly increases morbidity and mortality in older individuals. Several studies strongly suggest that female sex hormones influence the immune system. However, the impact of menopause on immune senescence remains poorly understood. To address this question, menopause was induced surgically in adult and aged female rhesus macaques by bilateral oophorectomy. Our studies show that ovariectomized adult female rhesus macaques generate a lower antibody and T cell responses following vaccination than age-matched cycling females. Furthermore, ovariectomized female rhesus macaques have increased frequency of CD8CD28- T cells, which suggest accelerated T cell senescence. Estrogen replacement therapy (ERT) improved both T and B cell responses to vaccination in elderly oopherectomized female rhesus macaques whereas combined hormone replacement therapy had modest effects. These data suggest that ovarian senescence exacerbates immune senescence and that ERT can improve immune response to vaccination in aged postmenopausal females.
Cysteine Protease Activators of Plasma Chemoattractant Chemerin (92.4)
Authors: Cichy Joanna , Kulig Paulina , Stefanska Anna , Kantyka Tomasz , Zabel Brian A , Potempa Jan , Butcher Eugene C 
Published: January 2023

Abstract
Chemerin, a ligand for seven-pass transmembrane, G protein-associated receptor CMKLR1 requires C-terminal proteolytic processing to unleash its chemoattractant activity. Proteolytically-processed chemerin selectively attracts specific subsets of immunoregulatory antigen presenting cells, such as immature plasmacytoid dendritic cells (pDC) and macrophages that express CMKLR1. Chemerin is predicted to belong to the structural cathelicidin/cystatin family of proteins that comprise inhibitors of cysteine proteinases (cystatins). Cysteine proteinases of the papain-like family are well characterized proteolytic enzymes, best known for their role in intracellular proteolytic pathways. Nevertheless, recent studies show that lysosomal cathepsins can also exert their proteolytic activity at extracellular sites in secreted or cell surface-bound forms. Extracellular cathepsins contribute to a variety of pathophysiological processes, including inflammation and neoplastic progression. Homology between chemerin and cystatins suggests that chemerin interacts directly with cysteine proteases. In this work, we demonstrate that chemerin does not display substantial inhibitory activity against human cysteine proteases. Instead, chemerin was found to be a new substrate for these proteases. The interaction between chemerin and the proteases resulted in the generation of potent attractant activity, eliciting a robust chemotactic response by CMKLR1 transfectants as well as human blood-derived PDC. Our data demonstrate that cathepsins may contribute to immune responses through the recruitment of pDC.
Severe impairment of leukocyte recruitment into inflamed tissue of ppGalNAcT1-deficient mice (94.1)
Authors: Mueller Helena , Tenno Mari , Van Aken Hugo , Marth Jamey D. , Ley Klaus , Zarbock Alexander 
Published: January 2023

Abstract
P-selectin glycoprotein ligand-1 (PSGL-1) plays an important role in leukocyte recruitment. Its binding affinity to selectins is modulated by posttranslational modifications. The polypeptide N-acetylgalactosamine transferase-1 (ppGalNAcT1) initiates core-type protein O-glycosylation. To address whether the glycosylation of PSGL-1 by ppGalNAcT1 is important for leukocyte recruitment, we investigated leukocyte rolling and velocity in untreated and TNF-α treated cremaster muscles and autoperfused flow chambers comparing ppGalNAcT1-/-(Galnt1-/-) with WT mice. In untreated and TNF-α treated Galnt1-/- mice, leukocyte rolling was significantly reduced with markedly increased rolling velocity compared to control mice. Flow chamber experiments showed that Galnt1-/-- and WT-neutrophils had the same rolling velocity on E-selectin, but the rolling velocity of Galnt1-/--neutrophils on E-selectin/ICAM-1 was significantly elevated, suggesting that E-selectin-dependent neutrophil activation may be defective. Thioglycollate-induced peritonitis experiments with chimeric mice revealed that hematopoietic ppGalNAcT1 is important for leukocyte recruitment. These data show that the loss of ppGalNAcT1 led to reduced leukocyte rolling and recruitment and increased rolling velocity, suggesting a predominant role of ppGalNAcT1 in attaching functionally relevant O-linked glycans to PSGL-1.
LOX-1 is a novel mediator of acute lung inflammation (94.10)
Authors: Fu Jian , Cheng Lili , Liang Mei , Zhang Ping 
Published: January 2023

Abstract
Up-regulation of Lectin-like oxidized LDL receptor-1 (LOX-1) has been known to mediate oxidized LDL-induced vascular inflammation and atherogenesis. Even though there has been increasing evidence suggesting that LOX-1 may play an important role in chronic inflammation, the role of LOX-1 in acute inflammation and tissue injury remains largely unknown. In our present study, we assessed the role of LOX-1 in a mouse model of endotoxin-induced acute lung injury. We demonstrated that LOX-1 could act directly as a neutrophil adhesion molecule. Importantly, blockade of LOX-1 was able to inhibit neutrophil infiltration into the lung. Furthermore, LOX-1 appears to play an important role in mediating pro-inflammatory signaling. NF-κB activation, ICAM-1 expression and apoptotic signaling induced by endotoxin challenge in the lung were all significantly inhibited by LOX-1 blockade. Collectively, our results indicate that LOX-1 could be a multi-functional pro-inflammatory mediator that may play important role in both the induction and development of acute lung inflammation and injury. Our studies also suggest that LOX-1 may serve as a potential therapeutic target against septic shock.
CD98hc Enables B cell Clonal Expansion and Adaptive Humoral Immunity (94.11)
Authors: Cantor Joseph , Browne Cecille , Feral Chloe , Rickert Robert , Ginsberg Mark 
Published: January 2023

Abstract
Lymphocyte clonal expansion mediates adaptive immunity. Here we report that CD98hc enables humoral immunity by supporting B cell clonal expansion. Deletion of B cell CD98hc in mice through conditional gene targeting did not affect B cell compartmentalization, but did result in reduced antibody responses. The mechanism of this effect did not involve interference with early signaling from antigen receptors, but instead was due to total suppression of rapid B cell proliferation, and consequent inability to form plasma cells. CD98hc can mediate both integrin signaling and amino acid transport. Reconstitution with CD98hc mutants revealed that its integrin interaction is required and its amino acid transport function is dispensable for B cell proliferation. These data establish that CD98hc enables clonal expansion of B cells, show that this function is performed by support of cell proliferation through interaction with integrins, and suggest that adaptive immunity drove appearance of CD98hc and its ability to capacitate integrin signaling.
T cell trans-endothelial migration and homing to lymph nodes rely on Myosin-IIA mediated acto-myosin contractility (94.25)
Authors: Jacobelli Jordan , Friedman Rachel S. , Conti Mary Anne , Khan Omar , Sorensen Caitlin , Adelstein Robert S. , Krummel Matthew F. 
Published: January 2023

Abstract
T lymphocytes migrate from the vasculature into lymph nodes and tissues scanning for antigenic peptides on cell surfaces. How T cells migrate through different environments and switch between types of motility in response to different stimuli is not fully understood. We have previously shown that in vitro Myosin-IIA has a role in T cell migration by regulating the switch between fast amoeboid-like motility and slower mesenchymal-like motility. Here, using conditional knockout mice, we have studied the role of Myosin-IIA-dependent cytoskeletal contractility in the migration of primary T cells in vivo. While Myosin-IIA depleted T cells in the lymph node were motile, they did not achieve the same fast motility rates of control T cells. In addition, homing of T cells to lymph nodes was inhibited in the absence of Myosin-IIA. This resulted from inefficient trans-endothelial migration (TEM) of Myosin-IIA depleted T cells; specifically, Myosin-IIA contractility was important to squeeze the body of the T cell (containing the nucleus) through the endothelial cell layer. Overall, our results suggest a critical role for Myosin-IIA in promoting TEM and migration through constrictive environments, while migration within more 'permissive' environments is not strictly dependent on the function of this myosin motor.
This work was supported by the NIH (RO1AI052116) and the Leukemia and Lymphoma Society.
Expression of chemokine receptors implicated in skin-homing on Herpesvirus-specific CD8+ T-cells (95.14)
Authors: Hensel Michael T , Caka Selin E , Wald Anna , Koelle David M 
Published: January 2023

Abstract
HSV-2-specific CD8+ T-cells express high levels of cutaneous lymphocyte associated antigen (CLA) and the related E-selectin ligand (ESL). These mediate rolling adhesion to inflamed dermal endothelium. EBV- or CMV-specific CD8+ T-cells express low levels of CLA/ESL. Full arrest and diapedesis are mediated via the chemokine axis. Chemokine receptors implicated in skin homing include CCR4, CCR6, CCR8, CCR10, and CXCR3. We examined cell surface expression of these receptors on pathogen-specific, tetramer-positive CD8 T-cells and bulk CD4 and CD8 T-cells, using both cryopreserved and fresh PBMC. Our results confirm that amongst CD4+ cells, CLA+ cells selectively express CCR4 and CCR10, and extend these findings to bulk CD8+ cells. We did not, however, observe selective enrichment of CCR4 or CCR10 on HSV-2-specific CD8+ T-cells compared to bulk CD4+ or CD8+ T-cells. In contrast, we measured higher CXCR3 expression on HSV-2-specific CD8+ T-cells when compared to bulk CD4+ and CD8+ T-cells, or EBV- or CMV-specific CD8+ T-cells. This suggests HSV-2-specific CD8+ T-cells may utilize CXCR3 expression to home to infected skin lesions.
Support from: NIH Grant AI30731 and STD/AIDS Research Training Grant 5T32AI007140
Interleukin-7 receptor (IL7R) expression provides the potential for long-term survival of both CD62Lhigh central memory T cells and Th1 effector cells during Leishmania major infection (96.6)
Authors: Colpitts Sara L , Dalton Nicole M , Scott Phillip 
Published: January 2023

Abstract
Infection with the protozoan parasite Leishmania major induces a state of concomitant immunity wherein secondary immunity is dependent upon the persistence of the original pathogen. Our lab has described two populations of L. major-induced CD4+ T cells that contribute to immunity: CD62Lhigh central memory T (TCM) cells and CD62Llow effector T (TEFF) cells. To determine if the prosurvival cytokine interleukin-7 (IL-7) contributes to maintaining these T cells, we examined IL-7 receptor (IL7R) expression on CD4+ T cells activated during L. major infection. We found that TCM cells present in chronically infected mice expressed high levels of the IL7R. However, we also found that CD62Llow cells responding to L. major infection expressed the IL7R. A large percentage of the IL7Rhigh CD62Llow cells were Th1 cells, based on transcription at the IFN-γ locus and upregulation of the Th1 transcription factor T-bet. The upregulation of T-bet did not prevent IL7R expression by L. major-responding CD4+ T cells nor did the absence of T-bet result in increased IL7R expression. Finally, blockade of IL7R signaling inhibited delayed type hypersensitivity responses in immune mice challenged with L. major, indicating that IL7R signaling contributes to the maintenance of Teff cells. Thus, both TCM and Th1 effector cells can express the IL7R during chronic L. major infection, which provides a potential means for their long-term survival.
IL-15 and IL-21 Mediated Homeostatic Proliferation of Human CD8 Memory T cells (96.7)
Authors: Nguyen Huy , Weng Nan-ping 
Published: January 2023

Abstract
Accumulation of CD28- CD8 T cells is a hallmark of the age-related decline in immune response. IL-15, a common γ-chain (γc) cytokine, is critical for the homeostatic proliferation of memory CD8 T cells and is recently shown to be associated with the down-regulation of CD28 expression. IL-21 is a newly identified member of the γc family of cytokines that has been demonstrated to have pleiotropic effects, influencing T cell proliferation and function. In IL-15-stimulated human CD8 naive T cells, IL-21 has been shown to prevent down-modulation of CD28 expression and augment cell growth. Here, we analyzed the effects of IL-21 on IL-15-stimulated memory CD8 T cells. In comparison between CD28+ and CD28- memory CD8 T cells under IL-15 alone or with IL-21 in vitro in young and old donors, we found that IL-21 drives more IL-15-stimulated cells to enter cell division and undergo apoptosis and that IL-21 preferentially enhances IL-15-induced proliferation of the CD28+ subset of memory CD8 T cells over its CD28- counterpart. Furthermore, we showed that IL-21 delays the IL-15-induced CD28 down-regulation at the cell surface and mRNA level for memory CD8 T cells. These findings demonstrate that IL-21 can increase proliferation of CD28+ cells and delay the generation of CD28- cells in IL-15-stimulated memory CD8 T cells, suggesting a possible role of IL-21 as an antagonist to the IL-15-induced increase in CD28- CD8 T cells that occurs during aging.
Functional Characterization of CBAP in Controlling Bim-independent Hematopoietic Homeostasis (97.14)
Authors: Chiang Yun-Jung , Yen Jong-Young Jeffrey 
Published: January 2023

Abstract
The lifespan of hematopoietic cells is involved in controlling inflammation and autoimmune response. CBAP (Common Beta chain Associating Protein) is a newly annotated membrane bound protein and is identified to associate with Box II domain, highly conserved among cytokine receptor superfamily, of common beta chain (βc) of GM-CSF/IL-3/IL-5 receptor.
In GM-CSF withdrawal-induced cell death assay, CBAP is demonstrated to trigger apoptotic signal, which is involved in Bax/Bak activation, and could be blocked by overexpression of Bcl-2 protein. In order to characterize the biological role of CBAP in vivo, we created the CBAP-deficient mice in either wild-type (wt) or Bim-deficient genetic background. We find that CBAP deficient mice are viable and fertile. The targeted allele could be transmitted according Mendel's Law inside the family, suggesting there is no apparent reproductive defect. In addition, we find the alterations of haematopoietic homeostasis. CBAP-deficiency increased the numbers of T cells, B cells and dendritic cells in the peripheral lymphatic organs in both the wt- and Bim-/- background, suggesting CBAP plays a non-redundant role in regulating hematopoietic homeostasis. CBAP-deficient primary bone marrow-derived dendritic cells (BMDCs) are more resistant to GM-CSF withdrawal-induced cell death, suggesting the contribution of CBAP in the regulation of apoptosis. Taken together, these results suggest the potential role of CBAP in controlling death of hematopoietic cells as well as playing a redundant role of Bim-regulated cell death.
Effects of IL-2 and IL-15 on CXCR6 Expression and Cytokine Production by Human Lymphocytes (98.26)
Authors: Perna Avi , Yang Xifeng , Li Linda 
Published: January 2023

Abstract
The chemokine receptor CXCR6, also known as BONZO and STRL133, is a seven transmembrane G protein-coupled receptor, primarily expressed on a subset of T effector cells, NK and NKT cells. Initially characterized as a co-receptor for HIV and SIV, studies of the interaction with CXCL16 have elucidated the important role of CXCR6 in leukocyte chemotaxis. This study focused on the kinetic effects of IL-2 and IL-15 on CXCR6 expression and cytokine production by lymphocytes in vitro. Freshly isolated human peripheral blood mononuclear cells (PBMCs) were cultured in the presence of recombinant IL-2 (20ng/mL) or IL-15(100ng/mL) for 15 days. The cells were harvested at regular time points and CXCR6 expression was analyzed via polychromatic flow cytometry. The results indicated that both IL-2 and IL-15 were able to effectively upregulate CXCR6 expression. Compared to non-stimulated cells, the frequencies of CXCR6+ cells were significantly increased (from 5-6% to 14-17%) at day 4 with maximum levels (30-50% CXCR6+) observed from day 7-9. The CXCR6 expressing cells were mainly in the lymphoblastic cell population and all CXCR6+ cells expressed CD3. We then further studied cytokine production profiles of the CXCR6 positive cells. After additional 6 hours re-stimulation with PMA plus ionomycin (in the presence of monensin), cytokine production was examined by intracellular staining and flow cytometric analysis. We found that IFN-g production by CXCR6+ cells (30-80%) was potentiated compared to their CXCR6- counterparts (10-30%). Additionally, IL-2 and IL-15 stimulation attenuated the ability of cultured PBMCs to produce IL-2. Further cytokine profiles are under investigation.
CXCL11 and CXCL12 activates ERK1/2 and NF-kB in breast cancer cells via CXCR3, CXCR4 and CXCR7 (98.3)
Authors: Mosley Lasharon  D , Singh Rajesh , Sharma Praveen K , Singh Shailesh , Lillard, Jr. James W 
Published: January 2023

Abstract
Metastasis of breast cancer (BrCa) cells involves organ-specific homing for migration, invasion, adhesion, and survival at secondary sites. Chemokines, such as stromal cell-derived factor-1 (SDF-1; CXCL12) and interferon-inducible T cell α-chemoattractant (I-TAC; CXCL11), and their receptors CXCR4, CXCR7 (CXCL11 & CXCL12), and CXCR3, respectively, are believed to play crucial roles in this process by G protein coupled signaling events leading to the activation of transcription factors. Our study investigates the CXCL12:CXCR4/CXCR7 as well as CXCL11:CXCR3/CXCR7 interactions on pathways known to mediate transcriptional activation of BrCa cell invasion mechanisms. ImageStream analysis revealed that treatment of MCF-7 and MDA-MB-231 cell lines with either CXCL11 or CXCL12 resulted in the activation and translocation of ERK1/2 and NF-¿B to the nucleus. FACE assay analysis demonstrated that stimulation with these chemokines selectively induced ERK1/2 and NFκB phosphorylation through FAK-, Src-, and/or PI3K-dependent pathways. These findings suggest CXCL11 and CXCL12 differentially induce signal transduction through CXCR3, CXCR4, and CXCR7. [This study was supported by funds from the James Brown Graham Cancer Center, Smith & Lucille Gibson Endowment. and National Institute of Health Grants CA092078, CA086359, and MD00525.]
Relationship between the high expression of nuclear beta-catenin in dendritic cells from NOD mice and the pro-inflammatory phenotype of these cells (99.18)
Authors: Atay Safinur , Villard Marine , Martin Michael , Parnell Sarah , Kosiewicz Michele , Alard Pascale 
Published: January 2023

Abstract
Pro-inflammatory cytokines are increased during the active stages of Type 1 diabetes and play an important role in disease development in NOD mice. Furthermore, antigen presenting cells from NOD mice produce elevated levels of IL-12 and IL-6 due to a hyperactive NFκB. β-catenin, is an important protein involved in gene regulation, and was recently found to interact physically with NFκB and regulate its translocation in the nucleus. We, therefore, have begun to investigate the relationship between β-catenin expression and the pro-inflammatory phenotype of dendritic cells (DC) in diabetes-susceptible NOD mice.
We have found a dramatic increase in the levels of nucleocytoplasmic β-catenin in bone marrow-derived DC, not macrophages, from NOD mice. Moreover, the increased levels of nuclear β-catenin correlated with increased levels of nuclear NFκB upon LPS stimulation. Altogether, these data indicate that NOD DC overexpress β-catenin, which upon accumulation in the nucleus may interact with NFκB and contribute to the pro-inflammatory phenotype of these cells. Experiments using β-catenin siRNA or inhibitors are ongoing to determine the role that β-catenin plays in the pro-inflammatory phenotype of NOD DC, and assess whether β-catenin may be a potential therapeutic target for the prevention and/or treatment of Type 1 diabetes. Funded by KDRB.
Analysis of regulatory and effector T cell repertoires during MOG-EAE (99.7)
Authors: Liu Xin , Steeves Meredith A , Nguyen Phuong , Geiger Terrence L 
Published: January 2023

Abstract
How the repertoires of conventional (Tconv) and Foxp3+ regulatory T-cells (Treg) compare in the context of active autoimmune disease is poorly understood. We assessed regulatory and effector T-cell repertoires in experimental allergic encephalomyelitis (EAE) induced by immunization with myelin oligodendroglial glycoprotein (MOG). We produced retroviral transgenic mice in which all T-cells express a single TCRá, and Treg are distinguishable from Tconv by a GFP-Foxp3 transgene. Repertoire was analyzed by cloning and sequencing the TCRâ chains from sorted CNS or splenic T-cells in mice with or without EAE. This demonstrated both substantial receptor diversity as well as public and private dominant receptors. Under inflammatory conditions, the Tconv used a repertoire distinct from that of Treg, though the repertoires overlapped. The extent of this overlap was not significantly increased with immunization or when comparing CNS infiltrating versus splenic T-cells. Further, greater similarity existed when comparing Treg or Tconv between spleen and CNS than when comparing the different cell types within an organ. This suggests that site-specific conversion between Treg and Tconv is limited in the context of active EAE. A subset of Vâ8.2, Jâ2.7 TCR were cloned, transduced into T-cell hybridomas, and functionally analyzed. Virtually all CNS-infiltrating Vâ8.2, Jâ2.7+ Tconv were MOG-specific whereas only ~half of the CNS Treg were. In the spleen, few TCR were MOG-specific. Therefore both MOG-specific Treg and Tconv with distinct repertoires are concentrated within the CNS during EAE, though infiltrating Treg seemingly possess a broader spectrum of antigen specificities.
Contribution of memory and naïve B cells to myelin specific T cell function in relapsing remitting multiple sclerosis (99.8)
Authors: Harp Christopher T , Frohman Elliot , Monson Nancy L 
Published: January 2023

Abstract
B cell depletion therapy reduces numbers of B and T cells within the cerebrospinal fluid (CSF) of relapsing remitting multiple sclerosis (RRMS) patients, suggesting that reduction of CSF B cells modulates the T cell pool in RRMS. We hypothesized that T-B cell interactions are required in order for myelin reactive T cells to proliferate and secrete cytokines optimally, and that memory B cells would be more effective APCs than naïve B cells, because of their higher expression of co-stimulatory molecules and high affinity B cell receptors. To test this hypothesis, we sorted naïve (CD19+CD27-) and memory (CD19+CD27+) B cells from the peripheral blood of 12 treatment naïve RRMS patients, incubated them with autologous purified T cells in the presence of myelin-derived proteins or control recall antigens, and measured T cell proliferation and cytokine production. Both naïve and memory B cells elicited CD4+ and CD8+ T cell proliferation and IFN-gamma secretion to recall antigens, although memory B cells from these patients elicited greater myelin specific CD4+ T cell proliferation than naïve B cells. These data suggest that in a subset of RRMS patients, the memory B cell pool has an enhanced ability to induce activation of myelin specific T cells, most likely because the memory B cell pool is enriched for B cells that have undergone myelin specific affinity driven maturation. This work was supported by Teva Neuroscience.