bluuebunny/crossref_metadata_2025_split huggingface dataset:
The interaction of α9 integrin and its ligands provides microenvironments critical for the development of autoimmune arthritis (94.9)
Authors: Kanayama Masashi , Kon Shigeyuki , Kurotaki Daisuke , Nakayama Yosuke , Morimoto Junko , Uede Toshimitsu 
Published: January 2023

Abstract
It has been shown that osteopontin (OPN) is critically involved in various Th1 type immune-mediated disorders such as rheumatoid arthritis (RA) and multiple sclerosis. In this study, we demonstrated that the expression of both OPN and tenascin-C (TN-C), and its common receptor, α9 integrin are up-regulated at the pathological foci of autoimmune arthritis. The local production of OPN and TN-C in arthritic joints is due to mainly synovial fibroblsts and to the lesser extent synovial macrophages. Majority of synovial fibroblasts and a subpopulation of synovial macrophages express α9 integrin. Importantly, autocrine and paracrine interactions of α9 integrin on synovial macrophages and fibroblasts and its ligands differently contribute to the production of pro-inflammatory cytokines and chemokines. α9 integrin is also involved in the recruitment and accumulation of inflammatory cells, through interaction with vascular cell adhesion molecule-1 (VCAM-1). Inhibition of α9 integrin function with an inhibitory anti-α9 integrin antibody significantly reduces production of arthrogenic cytokines and chemokines and ameliorates on-going arthritis. Thus, we identified α9 integrin as a critical intrinsic regulator that control the development of autoimmune arthritis. These results suggest that α9 integrin serves as a novel therapeutic target for the treatment of autoimmune disorders including RA.
Do the lungs deliver naïve CD4 T cells to draining nodes? (95.13)
Authors: Caucheteux Stephane M , Paul William E 
Published: January 2023

Abstract
~80% of lung CD4 T cells express low levels of CD44, high levels of CD62L, CD45RB, CCR7 and CD127 consistent with their being naïve. When Rag2-/- TCR transgenic cells are transferred to syngeneic mice, naïve phenotype transgenic cells are found in the lung. These cells disappear rapidly upon treatment with FTY-720 but are still found in mice treated with anti-CD62L, implying they are part of the recirculating pool but do not require L-selectin to enter the lung. Upon intranasal immunization with low (1 μg) antigen dose, the response is limited to the nodes draining the airways. When these low antigen doses are used, responses are not efficient as shown by the persistence of naïve antigen-specific CD4 T cells in the non-draining nodes. Nonetheless, "naïve" antigen-specific cells are lost from the lung; they reappear as activated cells at about 2.5 days after immunization, a response that is inhibited by FTY720. These results indicate that primary responses occur in the organized draining lymphoid tissue, as would be expected, but imply that the afferent lymphatics may be an important source for the delivery of naive CD4 T cells from tissues to the responding lymph nodes.
The role of the Septin cytoskeleton in primary T cell migration (95.3)
Authors: Gilden Julia K , Krummel Matthew F 
Published: January 2023

Abstract
The highly-conserved Septin family of GTP-binding proteins form filamentous networks in many cell types and have been implicated in a variety cell-biological processes, including membrane partitioning, molecular scaffolding, cytoskeletal regulation, and vesicle trafficking. We have previously reported that Septins are required for the regulation of shape, rigidity, motility, and membrane dynamics of a T cell line. Here, we extend our findings to primary cells. We found that during transmigration of a T cell through an endothelial monolayer under laminar flow, T cell Septins formed 'ribs' coplanar with the endothelial cells, a structure that may play a stabilizing role at this cell-cell contact. Biochemical and microscopic evidence showed that septin localization was altered following stimulation through CCR7 and through the TCR. Septins also played a role in the proper trafficking of T cells in vivo. Taken together, these results support a role for Septins in shape changes throughout the life of a T cell.
Both CD62L (L-selectin) and β7 integrin are Required for the Induction of Chronic Colitis (95.4)
Authors: Ostanin Dmitry V. , Bao Richard , Grisham Matthew B 
Published: January 2023

Abstract
L-selectin and beta7 integrin are T-cell associated molecules that are important for cell trafficking. The objective of this study was to assess the role of T-cell-associated CD62L and β7 in the induction of chronic colitis. Naïve (CD45RBhigh) CD4+ T cells were flow purified from the spleens of wild type (WT) or CD62L-/-xβ7-/- double deficient (DKO) mice and transferred into immunodeficient RAG-1-/- recipients. Transfer of WT T-cells induced robust colitis at 8 wks (mean histological score±SEM: 13.2±0.6) whereas transfer of DKO T-cells induced little or no disease at 8 wks (2.9±0.7) and only mild colitis at 25 wks (8.2±2.1) post-transfer. Total CD4+ T-cell numbers were reduced in the colonic LP of DKO→RAG-/- vs. WT→RAG-1-/- mice at both time points; however intracellular staining revealed that the few DKO LP CD4+ T-cells at 8 and 25 wks still produced significant amounts of IFN-γ and IL-17 comparable to that produced by WT LP CD4+ T cells. Analysis of CFSE-labeled WT or DKO T-cells transferred into RAG-1-/- mice revealed a defect in short-term homing to the MLN and colonic LP, but not in the in vivo activation/proliferation. These data suggest that DKO T-cells fail to induce colitis because of defects in T-cell trafficking rather than defects in T-cell activation and production of pro-inflammatory cytokines (supported by PO143785 and CCFA1787).
Lymphocyte subset recruitment during an immune response differs between peripheral and mucosal lymphoid tissues (95.7)
Authors: Grailer Jamison J. , Conway Rochelle M. , Steeber Douglas A. 
Published: January 2023

Abstract
Lymphocyte recirculation through peripheral lymphoid tissue depends primarily on the adhesion molecules L-selectin and α4β7 integrin. While most naïve lymphocytes express both molecules, subset-specific differences exist. These differences, along with tissue-specific expression of vascular ligands, results in preferential migration patterns among subsets. In the present studies, lymphocyte subset migration into peripheral (PLN) and mesenteric lymph nodes (MLN) was examined following s.c. and oral immunization, respectively. Naïve CD4+ T cell migration into PLNs increased after s.c. immunization with KLH-alum, peaking at 72 h. Naïve CD8+ T cell migration started lower than CD4+ cells, but increased steadily following immunization, reaching equivalent levels after 7 days. By comparison, B cell migration increased little and plateaued after 24 h. Among memory/effector cells, CD8+ T cell migration increased gradually up to 5 days post-immunization, and decreased thereafter, while CD4+ T cells increased modestly and plateaued after 24 h. In contrast to activated PLNs, oral immunization with cholera toxin + KLH resulted in peak increases in migration of all T cell subsets into the MLN at 24 h post-immunization. Interestingly, no changes in migration into the Peyer's patches were observed. These results indicate that activated PLN and MLN have different recruitment kinetics for lymphocyte subsets.
Role of GIT2 in T cell migration and development (95.8)
Authors: Phee Hyewon , Mollenauer Marianne N. , Weiss Arthur 
Published: January 2023

Abstract
The G-protein-coupled receptor (GPCR)-kinase-interacting proteins (GIT) 1 and 2 are multi-domain proteins involved in diverse cellular processes. In fibroblasts, GIT is thought to regulate focal adhesion (FA) turnover, cell spreading, and motility through interaction with various proteins. In T lymphocytes, GIT interacts with PIX (Pak-interacting Rac/Cdc42 guanine exchange factor) and PAK (p21-activated kinase) and forms a trimolecular complex. Our understanding of the physiological roles of GIT in T cells is very limited.
To determine the role of GIT1 and GIT2 in vivo, we generated GIT1- and GIT2- deficient mice. GIT1 is highly expressed in the brain, heart and testes. GIT2 is the major isoform expressed in hematopoietic cells. We found that GIT1 deficiency increased lethality, leading to perinatal death within 1-2 days after birth with a defect in brain development. GIT2-deficient mice were born healthy at normal Mendelian ratios. Interestingly, GIT2-deficient splenic T cells showed increased basal and chemokine-dependent migration. Furthermore, immature double positive thymocytes from GIT2-deficient mice showed increased basal and chemokine-induced migration. Since migration of thymocytes in the thymus has been tightly linked to their development, we crossed these mice to TCR transgenic mouse lines to better define the alterations in T-cell development and function by limiting compensation by repertoire selection. We found that the transition from the CD4 and CD8 double positive stage to CD4 single positive stage was greatly inhibited in the thymus of TCR transgenic GIT2-deficient mice. We are currently testing the hypothesis that GIT2 deficient-thymocytes have an altered migratory behavior leading to a defect in CD4 single positive thymocyte development.
*H.P. is supported by the Leukemia and Lymphoma Society Special Fellow Award.
Type I IFN-induced chemokine production and the regulation of immune effector cell trafficking from the bone marrow during acute MCMV infection (96.4)
Authors: Crane Meredith J , Hokeness-Antonelli Kirsten L , Salazar-Mather Thais P 
Published: January 2023

Abstract
Monocytes/macrophages are key innate effector cells in the response against murine cytomegalovirus (MCMV) infection. Activation of the chemokine receptor CCR2 on the monocyte/macrophage surface directs cell trafficking. In CCR2-deficient C57BL/6 mice, fewer monocytes/macrophages enter MCMV-infected livers. Consequently, downstream antiviral responses, such as NK cell recruitment, are impaired. Experiments were performed to better understand the origin of this defect. We hypothesized that CCR2 activation on bone marrow monocytes is required for release into the circulation, thus regulating their availability to the liver. We have demonstrated that monocytes accumulate in the bone marrow and are diminished in the circulation of CCR2-deficient mice. NK cells also accumulate in the bone marrow of CCR2-deficient mice, suggesting that impaired monocyte responses inhibit NK cell release. Monocyte mobilization from the bone marrow is likely coordinated by expression of the CCR2 ligands CCL2, CCL7 and CCL12. These chemokines are produced by F4/80+ bone marrow cells and detected in the serum in a type I IFN-dependent manner. These results further support the central role for type I IFN and chemokine-chemokine receptor interactions in establishing effective antiviral immune responses during MCMV infection.
Supported by NIH R01CA-102708 and the Nicole Rosenthal Hartnett '91 Graduate Fellowship.
Unique immune regulation by alternatively spliced IL-4 (97.3)
Authors: Atamas Sergei P , Lockatell Virginia , Todd Nevins W , Luzina Irina G 
Published: January 2023

Abstract
We have previously shown that IL-4δ2, a naturally occurring in humans and other species splice variant of IL-4, competes with IL-4 for receptor binding and inhibits some of IL-4 effects on lymphocytes and monocytes. Numerous groups reported that the levels and the ratio of IL-4δ2 and IL-4 mRNAs change in immune, inflammatory, and infectious diseases. It has been suggested that recombinant human (rh) IL-4δ2 can be used therapeutically to neutralize the harmful effects of excess IL-4 in vivo, although it was not clear whether IL-4δ2 mRNA expressing cells secrete IL-4δ2 protein. Transfection of HEK293 or Jurkat cells with IL-4δ2-encoding constructs resulted in IL-4δ2 protein secretion confirmed by LC/MS, ELISA, and Western blotting. To investigate whether IL-4δ2 has no independent activity and acts only as an inhibitor of IL-4, we overexpressed human IL-4δ2 in mouse lungs. Adenovirus-mediated gene delivery of IL-4δ2 caused lymphocytic infiltration similar to that in IL-4-overexpressing mice, as well as proinflammatory/Th1 changes in pulmonary milieu, with the induced levels of TNF-α, IL-1, IFN-γ, IL-12p40, and MCP-1 significantly exceeding those induced by gene delivery of IL-4. Germline deficiency of STAT6 had no effect, whereas deficiency of IL-4Rα significantly attenuated IL-4δ2-induced or IL-4-induced changes in the lungs. Stimulation of primary human T cells or PBMC, but not fibroblasts or A549 cells, with rhIL-4δ2 induced phosphorylation of Jak1, Jak3, and Tyk2, but not of STAT6. IL-4δ2 potently induced production of MCP-1 in human T cells and upregulated IL-4δ2 mRNA production in an autocrine fashion by several hundred fold. Thus, IL-4δ2 is secreted as a protein, acts as a potent autocrine regulator of inflammation and immunity in an IL-4Rα-dependent STAT6-independent fashion, and is a potential novel target for future therapies.
PARP-14 mediates IL-4-enhanced metabolic function and survival of B cells (97.4)
Authors: Cho Sung Hoon , Boothby Mark 
Published: January 2023

Abstract
IL-4 is survival factor for lymphocytes and other hematopoietic cells. Whether there are mechanisms of pro-survival signaling induced by IL-4 apart from PI3K-Akt activation is not fully clear. Our laboratory identified PARP-14, a poly-ADP-ribose polymerase subfamily member, as a Stat6-interacting protein. PARP-14 is highly expressed in lymphoid organs, influences B cell subset ratios as well as the IgA response to antigen, and has intrinsic ADP-ribosyltransferase activity. ADP-ribosyltransferases and PARPs catalyze mono- and poly-ADP-ribosylation, transferring ADP from NAD+ to target proteins. ADP-ribosylation is a post-translational modification used by bacterial exotoxins to impact signal transduction, or, in the case of the mammalian PARP-1, to influence gene transcription and DNA repair or trigger apoptosis. Almost nothing is known about biological roles or mechanisms of action of other mammalian PARPs. We now show that PARP-14 is essential for full survival signaling despite normal Akt activation in B cells. Investigation of the mechanism(s) revealed that PARP-14 mediates IL-4 induction of gene products known to promote cell survival, and also metabolic functions of B cells. Moreover, intervention that restored glycolytic activity in IL-4-treated B cells also rescued pro-survival signaling. These results reveal a novel link to metabolic regulation via a mammalian ADP-ribosyltransferase.
Helicobacter pylori Induces Gastric Epithelial Cell Production of TGF-β that Suppresses CD4+ T Cells (97.7)
Authors: Beswick Ellen J , Pinchuk Irina V , Schmitt David A , Reyes Victor E 
Published: January 2023

Abstract
CD4+ T cells are recruited to the gastric mucosa during H. pylori infection, but are generally hyporesponsive. CD4+CD25+FoxP3+ regulatory T cells (Treg) are present during infection and impact the CD4+ T cell response. We have previously shown that epithelial cell responses to H. pylori play an important role in inhibiting CD4+ T cell responses via the local induction of Treg cells from naïve CD4+ T cells. As TGF-β plays a role in the development of Tregs, we hypothesized that gastric epithelial cells (GECs) produce TGF-β during H. pylori infection that contributes to Treg development and suppresses local CD4+ T cell effector function. In order to investigate this, we examined GEC production of TGF-β after exposure to H. pylori and found them to produce significant levels of TGF-β that were partially dependant on the cag PAI virulence factor of H. pylori. TGF-β produced by GEC in response to H. pylori increased the local development of CD4+CD25+FoxP3+ Treg cells from naïve T cells in co-culture with GEC and decreased proliferation of activated CD4+ T effector cells in co-culture with GEC. These events were decreased when TGF-β neutralizing antibodies were present. The observations presented here introduce a novel mechanism used by H. pylori via gastric epithelial cells leading to inhibition of CD4+ T cells that may contribute to chronicity of infection.
CCR1 expression and signal transduction by murine BMMC results in secretion of TNF-α, TGFβ-1 and IL-6 (98.10)
Authors: Fifadara Nimita , Aye Cho Cho , Raghuwanshi Sandeep , Richardson Ricardo , Fukuda Ken , Ono Santa 
Published: January 2023

Abstract
Chemokine receptors are important co-stimulatory molecules found on many blood cells. Chemokine receptor 1 (CCR1) is one of the important chemokine receptor identified in different immune cells known for its function in various diseases. The expression and functions of chemokine receptors on mast cells has been quite controversial. In this study, we report for the first time that murine bone marrow-derived mast cells (BMMC) express mRNA and protein for CCR1. BMMC cultured in the presence of murine recombinant stem cell factor and murine interleukin-3 expressed CCR1 after 5-6 weeks. Co-stimulation of CCR1 by its ligand macrophage inflammatory protein 1α (MIP-1α) and the IgE receptor FceRI enhanced BMMC degranulation compared to FceRI stimulation alone (85% vs. 54%, p &lt; 0.0001) and Ca2+ influx. We report for the first time that mBMMCCCR1+ cells endogenously express neurokinin receptor-1 and intercellular adhesion molecule-1. We also observed significant increases in mast cell secretion of key growth factors, cytokines and chemokine mediators upon CCR1- FceRI co-stimulation. These factors include transforming growth factor β-1, tumor necrosis factor-α, ciliary neurotrophic factor and the cytokine interleukin-6. Taken together, our data indicate that CCR1 plays a key role in BMMC function. These findings contribute to our understanding of mechanisms for immune cell trafficking during inflammation.
The effect of interleukin-32 gamma on the differentiation of osteoclasts from CD14+ monocytes (98.15)
Authors: Lee Chang-Keun , Kim Yong-Gil , Kim Soo-Hyun , Lee Sang-Heon , Yoo Bin 
Published: January 2023

Abstract
IL-32 induced various cytokines including TNF-a in monocytes and differentiation of monocytes into macrophage-like cells. However, the effect of IL-32 on differentiation of monocytes into osteoclasts is still unknown. Our study was designed to evaluate whether IL-32 affects on osteoclasts differentiation and how this cytokine modulates the receptor activator NF-κB ligand (RANKL) and osteoprotegerin (OPG) on fibroblast-like synoviocytes (FLS).
CD14+ monocytes were isolated from healthy volunteers and FLS were isolated from synovium of RA patients. To test of osteoclastogenic effect, IL-32γ (0 as control, 25, 50, 100-ng/ml) or IL-17 (20-ng/ml) were treated in the monocytes culture system and Osteologic disks® with M-CSF and sRANKL for 2-week. To evaluate RANKL and OPG changes in FLS by IL-32γ or IL-17 (0, 3, 5-day), the mRNA expression and protein level were evaluated using RT-PCR and ELISA.
After 2-week culture, the osteoclasts count and the resorbed area on Osteologic disks® were increased significantly in 50-ng/ml IL-32γ group more than those in IL-17 group (p &lt; 0.01 and p &lt; 0.05). Increased level of RANKL and decreased level of OPG were observed prominently in IL-32γ stimulated group compared with IL-17 stimulated group at 5-day.
Our results suggest IL-32γ is a potent osteoclastogenic cytokine and could make more favorable condition for osteoclastogenesis in RA synovium via RANKL and OPG modulation in FLS.
CXCL11 and CXCL12 mediate matrix metalloproteinase expression by breast cancer cells through CXCR7 (98.2)
Authors: Mosley Lasharon  D , Sharma Praveen K , Singh Rajesh , Singh Shailesh , Lillard, Jr. James W 
Published: January 2023

Abstract
Chemokines and their receptors have been implicated in organ-specific homing of metastatic breast cancer (BrCa) cells. Stromal cell-derived factor-1 (SDF-1; CXCL12), a homeostatic chemokine, has been suggested to promote BrCa progression. Interferon-inducible T cellα-chemoattractant (I-TAC; CXCL11), an inflammatory chemokine, is elevated following IL-1, TNF-α, IL-6, and/or IFN-γ stimuli, which are increased during breast tumor burden. In this study, we focused on CXCL12 and its receptors, CXCR4 and CXCR7, as well as CXCL11 and its receptors, CXCR3 and CXCR7. RT-PCR and ImageStream analysis demonstrated that MCF-7 and MDA-MB-231 cell lines differentially express CXCR3, CXCR4, and CXCR7. CXCL11 stimulation modulated matrix metalloproteinase (MMP) expression via CXCR7 &gt;&gt; CXCR3 interaction; similarly, CXCL12 increased MMP-1, MMP-13, MMP-2, and MMP-9 mRNAs and active protein expression in a largely CXCR7-dependent fashion. These CXCR7-required events were significantly altered by selective Gαi protein subunit and Gβ/γ protein subunit(s) inhibition. Taken together, these studies provide novel information regarding the cellular and molecular mechanisms involved in CXCR7-mediated BrCa progression. [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.]
Nanonized black soybean enhances immune response in senescence-accelerated mice (98.20)
Authors: Jeng Kee Ching G. , Chan Yin-Ching , Wu Chia-Chuan , Chan Kung-Chi , Lin Yo-Giao , Liao Jiunn-Wang 
Published: January 2023

Abstract
This study investigated the effect of soybean supplementation on the immune response in the senescence-accelerated-prone mice (SAMP8) and -resistant mice (SAMPR1, control). Male SAMP8 mice (6 mo old) were supplemented with or without nanonized (Nano-soy) or microparticled (Micro-soy) black soybeans (n = 8/group), respectively for 12 wk. Human PBMC and murine splenocytes were stimulated with mitogens and cytokines were determined by RT-PCR and/or ELISA. The results showed that food intake was similar among all groups. Isoflavone (daidzin and genistin) intake was higher in the Nano-soy group than the Micro-soy group. The lymphoproliferation and production of IL-2 and IFN-γ in the Nano-soy group had a significantly higher (P &lt; 0.05) than those in the control and Micro-soy groups. The Nano-soy group mice reached these cytokine levels similar to SAMR1 mice. This result was consistent with the in vitro data that daidzein (a metabolite of daidzin), at a concentration of 10 μM, increased IL-2, IL-4, and IFN-γ production from PHA-stimulated PBMC (P &lt; 0.05). However at higher dose (&gt; 50 μM), daidzein only reduced IL-10 and IFN-γ levels, whereas genistein reduced levels of the IL-2, IL-4, IL-10, IFN-γ mRNA and protein. This suggests that the Nano-soy supplementation improved immune response in SAMP8 mice which may be attributable to higher daidzin content in the diet.