bluuebunny/crossref_metadata_2025_split huggingface dataset:
The expression level of autoantigen TRIM21 changes during lymphocyte development (84.10)
Authors: Yoshimi Ryusuke , Chang Tsung-Hsien , Wang Hongsheng , Atsumi Toru , Morse III Herbert C. , Ozato Keiko 
Published: January 2023

Abstract
The tripartite motif (TRIM) family member, TRIM21, is an E3 ubiquitin ligase that functions in both innate and acquired immunity. It is also an autoantigen known as Ro52/SS-A. While TRIM21 is thought to be ubiquitously expressed, its precise distribution patterns among various tissues and cells are largely unknown. To analyze detailed expression patterns of TRIM21, we generated mice with the Trim21 gene replaced by an EGFP reporter. Western blot data showed that EGFP is expressed particularly at high levels in lymph nodes, spleen and thymus. Flow cytometric analyses using splenocytes demonstrated that EGFP expression was generally high in T cells, macrophages and DCs, but lower in B cells and granulocytes. During B-cell development in bone marrow and spleen EGFP levels were high in pro-B cells, but fell in the subsequent stages until small pre-B cells and then rose again in later stages of development. During T-cell development in thymus EGFP expression was high in early CD4-CD8- double negative cells, and the expression gradually decreased as cells moved through mid to late stages of double negative cells and became much lower in double positive cells. Then EGFP expression rose again during the subsequent stages of single positive cells. These data suggest that TRIM21 may have a functional role during lymphocyte development.
Role of cFLIP in the initiation and maintenance of the germinal center response (84.18)
Authors: Coffey Francis J , Manser Tim 
Published: January 2023

Abstract
During a T cell-dependent immune response, B cells are activated and accumulate in germinal centers where they proliferate, undergo somatic hypermutation, and stringent clonal selection. These events are essential to the production of high affinity antibody responses and long-lived memory B cell populations. Apoptotic pathways are believed to play a pivotal role in regulating the expansion of activated B cells and negative selection events operative in germinal centers. Increased levels of the death receptor Fas on germinal center B cells should make them highly sensitive to Fas-induced cell death. However, previous studies have suggested a role for increased levels of cellular FLICE-inhibitory protein (cFLIP) in preventing Fas-mediated apoptosis in germinal center B cells. Therefore, regulation of cFLIP expression may important to the maturation of the immune response and the maintenance of peripheral tolerance. In the present study, we utilize mice with a B cell-specific deletion of cFLIP to assess its requirement during a T-dependent immune response. Analysis of bone marrow and splenic B cell populations in these mice indicates that there is no apparent maturation defect, despite a mild B cell-specific lymphopenia. However, data from immunization studies with various T-dependent antigens suggests an important role for cFLIP expression in the expansion of antigen-specific B cells and their participation in the germinal center response.
This work is supported by T32CA09683 to F.C. and AI038965 to T.M.
Mcl-1 promotes T cell survival independently of Bcl-2 through interaction with Bak (84.19)
Authors: Dunkle Alexis D , Dzhagalov Ivan , He You-Wen 
Published: January 2023

Abstract
T cells depend on the careful regulation of apoptosis for normal development, homeostasis and immune response. The Bcl-2 family of proteins has been shown to play critical roles regulating T cell apoptotic pathways. The anti-apoptotic proteins Bcl-2 and Mcl-1 each display a unique expression pattern throughout the lifespan of a T cell and both have been shown to be essential for T cell survival at multiple stages. However, it is unclear whether these proteins function in the same or separate molecular pathways. Here, we use genetic models to show that Mcl-1, through antagonism of Bak, has a unique function from Bcl-2 at multiple stages of thymocyte development. Loss of Bak rescues the death of Mcl-1-deficient thymocytes at the double negative and single positive stages. Loss of Bax, however, does not rescue Mcl-1-deficient thymocytes. Neither over-expression of Bcl-2 nor loss of the BH3-only protein Bim rescues the death of Mcl-1-deficient thymocytes. Interestingly, loss of Bak does not rescue activated T cells in an in vitro Mcl-1 deletion system, thus mechanisms may differ at different stages. These data indicate non-overlapping and distinct roles for Mcl-1 and Bcl-2 in T cells.
This work was supported by grants from the NIH.
Role of Itk in γδ T cell development and function (84.22)
Authors: Yin Catherine C , Felices Martin , Kosaka Yoko , Kang Joonsoo , Berg Leslie J 
Published: January 2023

Abstract
In conventional αβ T cells, the Tec family tyrosine kinase Itk is required for signaling downstream of the TCR. Itk also regulates αβ T cell development, lineage commitment, and effector function. A well established feature of Itk-/- mice is their inability to generate T helper type 2 (Th2) responses that produce IL-4, IL-5, and IL-13; yet these mice have spontaneously elevated levels of serum IgE and increased numbers of germinal center B cells. Here we show that the source of this phenotype is γδ T cells, as normal IgE levels are observed in Itk-/-Tcrd-/- mice. Further, we find that γδ T cells numbers are increased in Itk-/- mice, along with elevated proportions of γδ T cells expressing CD4 and NK1.1. When stimulated through the γδ TCR, Itk-/- γδ T cells produce high levels of the Th2 cytokines, but diminished IFNg. In addition, activated Itk-/- γδ T cells upregulate costimulatory molecules important for B cell help, suggesting that they may directly promote B cell activation and Ig class switching. Together, these data indicate that Itk signaling regulates γδ T cell lineage development and effector function, and is required to control IgE production in vivo.
Expression of CD226 Antagonizes Apoptotic Cell Death in Murine Thymocytes (84.4)
Authors: fang liang , Zhang Xinhai , Miao Jun , Zhao Fang , Yang Kun , Yang Angang , Chen Lihua , Jin Boquan 
Published: January 2023

Abstract
CD226 is known to be expressed on many types of peripheral lymphoid cells and involved in T cell differentiation, activation, and cytotoxicity. We found that CD226 was also expressed on mouse thymocytes at varying developmental stages, and its expression was associated with resistance of thymocytes against apoptosis. Expression of CD226 appeared to be closely coupled with thymocyte development, in that CD226 was preferentially expressed on CD4+CD8- and CD4-CD8+ thymocytes at all stages during mouse development. In DP, mainly expression of CD226 on CD69+ thymocytes showed that CD226 may be involved in positive selection. Inhibition of CD226 by shRNA in a fetal thymus organ culture (FTOC) model resulted in reduced thymus cellularity, which was associated with enhanced apoptotic cell death in the thymus as evidenced by the increased cell number with externalization of phosphatidylserine and increased caspase-3 activity. In contrast, CD226 transgenic mice displayed enlarged thymus and increased thymus cellularity. Expression of CD226 seemed to be associated with expression of survivin in that inhibition of CD226 down-regulated survivin expression and activition, and over-expression of CD226 rescued thymocytes from apoptosis through activition of survivin. Taken together, that CD226 is an anti-apoptotic molecule that may play an important role in murine thymus development.
NKAP, a novel modulator of Notch signaling, is required for T cell development (85.5)
Authors: Shapiro Virginia Smith , Pajerowski Anthony , Nguyen Chau , Aghajanian Haig , Shapiro Michael J. 
Published: January 2023

Abstract
T cell development depends on the coordinated interplay between receptor signaling and transcriptional activation/repression. We performed a genetic complementation screen, and identified a novel transcriptional repressor, NKAP. NKAP associates with HDAC3 and is part of a DNA-binding complex, as shown by chromatin immunoprecipitation. NKAP also associates with CIR, a part of the Notch corepressor complex. The expression of NKAP during T cell development inversely correlates with the expression of Notch target genes, implying that NKAP may modulate Notch-mediated transcription. To examine the function of NKAP in T cell development, Lck-cre NKAP conditional knockout mice were generated. Interestingly, loss of NKAP blocks development of alpha/beta but not gamma/delta T cells. In addition, lck-cre NKAP cKO DP T cells express 8- to 20-fold higher levels of Hes1, Deltex1 and CD25, providing in vivo evidence that NKAP functions as a transcriptional repressor, acting at least in part, by repression of the Notch pathway.
Cross-talk between IL-7Ra signaling and p53 pathway during thymopoiesis and lymphomagenesis (86.8)
Authors: Kibe Ryoko , Zhang Shu-zhong , Marrero Luis , Khan Shafin , Zieske Arthur , Huang Jiaqiang , Durum Scott K , Iwakuma Tomoo , Cui Yan 
Published: January 2023

Abstract
Thymopoiesis in IL-7Rα-/- mice is blocked at the CD4-CD8- double negative stage with failures in T cell receptor (TCR) γand β rearrangement. Early studies suggest that unsuccessful TCRβ rearrangement in mice defective in DNA damage repairs, incurring DNA double-strand breaks, results in p53 activation. However, it remains unknown whether p53 plays a role in the thymopoietic defect in IL-7Rα-/- mice. In this study, we demonstrated that p53 is highly activated in the thymocytes of IL-7Rα-/- mice. Considering the importance of p53 activity during TCR rearrangement and the observation of incomplete rescue of thymopoiesis in IL-7Rα-/- mice by modulating activities of Bcl-2 family members, we hypothesize that p53 activation may also contribute to the impaired thymopoiesis in IL-7Rα-/- mice and that temporal suppression of p53 activity by the IL-7Rα signaling facilitates thymopoiesis. With the generated IL-7Rα-/-p53-/- (DKO) mice, we found that p53 inactivation in IL-7Rα-/- background resulted in a 30-fold increase in thymic cellularity with increased TCRβ? cells. Furthermore, DKO mice developed thymic lymphoma at a higher incidence and died significantly earlier than p53-/- mice. Our study is the first to illustrate a functional interplay between IL-7Rα signaling and p53 pathways in facilitating TCRβ+ T cell development during thymopoiesis and lymphomagenesis.
Osteoclasts activation by receptor activator of NF-κB ligand (RANKL) enhanced the mobilization of hematopoietic progenitor cells from the bone marrow in acute injury (87.10)
Authors: CHO KYUNG-AH , Ju Sun-Young , Ryu Kyung-Ha , Woo So-Youn 
Published: January 2023

Abstract
Osteoclasts (OCLs) are specialized cells responsible for physiological bone resorption and as well as pathologic bone loss. In addition to unique ability to resorb bone, OCLs also play potential role in the mobilization of hematopoietic progenitor cells from bone marrow, particularly under various stress stimuli(e.g. hypoxia, injury or inflammation). We investigated effect of activated OCLs on the stem niche whether lead to mobilization of hematopoietic progenitors under liver specific injury, which was established in our previous acute liver disease study. We exposed mice to stress situation by inducing liver injury with CCl4 or combination of additional injecting of RANKL to activate OCLs, and compared the effect on the mobilization of hematopoietic progenitor cells from the BM. To investigate OCLs involved mechanism underlying mobilization, we induced activated OCLs from RAW 264.7 cell line through stimulation with RANKL and quantified the level of stem cell niche component, SDF-1 on the osteblasts and CXCR4 on the bone marrow cells(BMCs), after culturing with supernatants from activated OCLs. As a result, Under the stress situation in vivo, the mobilized hematopoietic progenitor cells were significantly increased after RANKL treatment under liver specific injury. Moreover, we found that functional OCLs cleaved SDF-1α on the osteoblasts and increased CXCR4 expression on the BMCs in vitro. These results suggest that OCLs might be involved in alteration of the interaction between SDF-1 and CXCR4 leading to mobilization of hematopoietic progenitor cells from the BM.
Disease stage-related changes in T cell receptor-VB profile in cutaneous T cell lymphoma (88.10)
Authors: Pomerantz Rebecca G , Patton, Jr Timothy J , Donnenberg Albert D , Mirvish Ezra D , Falo, Jr Louis D , Geskin Larisa J 
Published: January 2023

Abstract
The objective of this study was to evaluate the T cell receptor-Vβ (TCR-Vβ; Vβ) repertoire in patients with Mycosis Fungoides (MF) and Sezary Syndrome (SS) variants of cutaneous T cell lymphoma (CTCL) across all stages, in order to identify relationships between Vβ expression levels and disease stage. Blood was drawn from MF/SS patients (n=31) and the percentage of CD4+ T cells expressing each Vβ was determined by multiparameter flow cytometery and the change in expression levels with progressive disease stage was calculated with Spearman's rank correlation coefficients. We found that individual TCR-Vβ families were expanded in some patients with advanced MF/SS. Further, we detected significant decreases in the proportion of five TCR-Vβs with progressive stages of disease, while the proportion of all other tested TCR-Vβ families did not change with disease stage. These data show disease stage-related changes in the expression of certain TCR-Vβs known to be activated by viral superantigens. In particular, there was a highly significant decrease in expression of TCR-Vβ13, which has been found to be activated by an EBV-associated superantigen, in advanced CTCL. Based on these findings, we theorize that in early stages of CTCL, viral infection may play a role in the expansion of specific superantigen-associated T-cells; while in later stages, these same T-cells become eliminated by a yet unknown mechanism.
Funding Sources: National Institutes of Health, Dermatology Foundation, University of Pittsburgh Clinical & Translational Research Center
Preventive effects of Paeonol on cisplatin induced nephrotoxicity in mice (88.12)
Authors: Lee Hyojung , Yu Gun , Lee Hyoeun , Hong Moo-Chang , Shin Min-Kyu , Kim Yangseok , Bae Hyunsu 
Published: January 2023

Abstract
Paeonol, a major phenolic compound of Moutan Cortex, was known that to have antioxidant and anti-inflammatory activities. Cisplatin is a chemotherapeutic agent, however, its nephrotoxicity limits the use of this drug. In the present research, we examines whether paeonol has protective effects on cisplatin induced acute renal failure in mice. Animals were given 20mg/kg of paeonol intraperitoneally for 3 days. At 4 days, all groups of mice received a single dose of cisplatin at 30mg/kg intraperitoneally. Paeonol treated group marked attenuation in serum creatine, BUN, and survival. Paeonol treated group had a significantly reduced the levels of proinflammatory cytokines when compared to the control group. These results demonstrated that Paeonol pre-administration can prevent the renal toxic effects of cisplatin.
The role of transforming growth factor-beta signaling in a murine model of lung cancer (88.16)
Authors: Soó-Becker Kinga , Zhivkova Nataliya , Boross Ildikó , Koslowski Michael , Wiewrodt Rainer , Türeci Özlem , Lehr Hans A. , Finotto Susetta 
Published: January 2023

Abstract
The transforming growth factor beta TGFβ is known to be a potent tumour suppressor at early stages of cancer. However, cancer cells can lose responsiveness to TGFβ through mutations in the signaling pathway downstream of the TGFβ receptor.
TGFβ influences the development of regulatory T cells known to enhance cancer development. We analyzed TGFβ expression in the lung of subjects affected by lung adenocarcinoma. TGFβ mRNA level was increased in the lung of these patients and this value correlated with the progression of the disease. We thus asked whether targeting TGFβ signalling in T cells would inhibit regulatory T cells in a murine model of lung adenocarcinoma. Mice that overexpress a dominant negative form of TGFβ type II receptor lacking the cytoplasmic kinase domain in T cells were used. Histologically, we found a tumour regression in the abscence of TGFβ signalling in T cells. A hyperproliferation of the CD4+ T cells overproducing interferon gamma (IFNγ) was observed. Analysis of the regulatory T cells showed an intact supression function of these cells.
In summary, a defective TGFβ-signalling in lung T cells could lead to amelioration of lung adenocarcinoma in mice because inducing hyperproliferation of IFN-gamma producing CD4+ T cells thus limiting the T regulatory component in this disease.
This work is supported by the GK1043 in Mainz.
Genetic Approach to Study Complement Role in Ovarian Cancer (88.24)
Authors: Nunez-Cruz Selene , Connolly Denise , Roberts Amber , Markiewski Maciej , John Lambris D , Coukos George , Scholler Nathalie 
Published: January 2023

Abstract
The complement system plays a crucial role in inflammation, which is known to contribute to carcinogenesis and tumor progression. However, the exact role of complement in cancer development remains poorly understood. We investigated the contribution of complement to the development of ovarian carcinoma (OC). OC is the second most common gynecologic cancer and the fourth leading cause of cancer death in women. We assessed the influence of complement on angiogenesis and tumor microenvironment by crossing complement component 3 knockout (C3KO) with transgenic mice expressing the Simian Virus 40 TAg under the control of the Müllerian Inhibiting Substance type II Receptor promoter (MISIIR-TAg). MISIIR-TAg mice develop bilateral OC resembling human serous OC with ~100% penetrance.
We found that C3KO/MISIIR-TAg mice exhibited reduced tumor volume and microvessel formation compared to control wild-type C3 and C3 heterozygote (C3HET) littermates. In addition, we found that tumor-infiltrating macrophages, B cells and T lymphocytes from C3KO/MISIIR-TAg mice produced significantly less cytokines after ex-vivo culture. Furthermore, the number of CD3+/CD4+/FoxP3+ T-cells was reduced in these mice. These results support the hypothesis that C3 plays an important role in tumor progression and vascularization, and that complement deficiency might compromise tumor-infiltrating leukocyte functions.
This work was supported by P01 AI 068730 (NIH/NCI)
Neuropilins bind TGF-beta and its receptor components and promote Smad signaling (88.5)
Authors: Prud'homme Gerald J. , Stoilova Snejana , Glinka Yelena 
Published: January 2023

Abstract
Neuropilin-1 (Nrp1) and/or neuropilin-2 (Nrp2) are expressed by many tumors, correlating with a poor prognosis. Normally, Nrp1 is expressed by neurons, endothelial cells, dendritic cells (DCs) and Treg cells, while Nrp2 has a more limited distribution. Because neuropilins are coreceptors for VEGF, it has been thought they stimulate tumor angiogenesis, but they may also act otherwise. We recently reported that Nrp1 binds and activates LAP-TGF-beta1 (the latent form) and enhances Treg activity. Here, we report that both Nrp1 and Nrp2 interact with TGF-beta1, as well as TGF-beta receptor components, and induce internalization of the TGF-beta receptor complex. This enhances signaling by the Smad pathway. In accord with this, we found that both Nrp1 and Nrp2 activate latent TGF-beta1 on the membrane of breast cancer cells. The classical TGF-beta receptors (RI, RII and RIII) only bind active TGF-beta, but our data suggest that the neuropilins allow responsiveness to latent TGF-beta by its activation. We also find that TGF-beta competes with VEGF for binding to Nrp1/Nrp2, possibly altering angiogenesis. TGF-beta has been linked to metastasis and, thus, the neuropilins may promote metastasis by capturing and activating latent TGF-beta. Our novel findings are relevant to cancer biology, immune regulation and angiogenesis. This work was funded by the Ontario Institute for Cancer Research, Province of Ontario, Canada.
Signaling model of cell death shows cell-to-cell stochastic fluctuations are linked to apoptosis related diseases (88.8)
Authors: Raychaudhuri Subhadip 
Published: January 2023

Abstract
We have developed a detailed computational model of apoptotic cell death signaling that could explain some of the recent experimental observations on apoptosis (Goldkorn et al. Antioxid. Redox Signal, 2005). Specifically, our results show how apoptosis signaling can be slow (~ 10 hours) under weak stimulus due to large cell-to-cell stochastic fluctuations through the type 2 pathway of signaling. We use a novel set of stochastic differential equations to elucidate a robust network design and stochastic effects in apoptosis signaling in a cell-type independent manner. However, apoptosis signaling and diseases that arise from aberrant apoptosis signaling are often cell-type specific. For example, recent experiments have revealed neuroglobin protein as a novel inhibitor of the apoptotic pathway (T. Brittain et al., FEBS Letters, 2006) that has 1000 fold higher concentration level in neural and retinal cells (~ 100 micro-molar) compared to its 10-100 nanomolar concentration in most other cell types. We use our computational model to show that stochastic signaling through the type 2 pathway can explain the presence of such disparate levels of neuroglobin amount depending on the cell type. We also propose a molecular mechanism of apoptosis related diseases, such as degenerative disorders and cancer, due to aberrant signaling through the stochastic type 2 pathway and a faulty type 2 to type 1 switching of apoptotic signaling. A role of aberrant expression of apoptotic inhibitor Bcl2 in such apoptosis related diseases are also discussed.
Peptide-induced peripheral T cell deletion leads to tolerance mediated by TRAIL-expressing CD8+ regulatory T cells (89.16)
Authors: Gurung Prajwal , Ferguson Thomas A , Griffith Thomas S 
Published: January 2023

Abstract
Peripheral tolerance controls self-reactive T cells that escape thymic deletion. We previously showed that deletion of Ag-specific CD4+ T cells after soluble Ag injection leads to immune tolerance mediated by a CD8+ Treg population in response to the processing and presentation of the apoptotic T cells by the immune system. The CD8+ Treg maintain long-term tolerance to subsequent Ag challenge by deleting T cells that share the same Ag specificity. The present study explored the mechanism of action of these CD8+ Treg. Our data show OT-II T cells expand and contract equally in wildtype (WT) and TRAIL-/- mice after OVA323-339 injection. After contraction, WT mice were tolerant to subsequent OVA/CFA immunization, even when given fresh OT-II T cells, but TRAIL-/- mice displayed immunity. Analysis of the tolerant B6 mice found the transferred OT-II T cells did not undergo secondary expansion after OVA/CFA immunization, but secondary T cell expansion was evident in the non-tolerant TRAIL-/- mice. Subsequent investigation found direct killing of freshly transferred OT-II T cells in a TCR-specific manner in tolerant WT mice, but not in TRAIL-/- mice, and only CD8+ T cells from tolerant WT mice could transfer tolerance to naïve recipients. These data provide evidence for a novel mechanism of peripheral tolerance maintained through the cytotoxic activity of TRAIL-expressing CD8+ Treg against T cells of the same Ag specificity.