bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dysregulation of ERK signaling in CD4-expressing cells induces osteochondromas (IRC8P.441)
Authors: Wehenkel Marie , Corr Maripat , Edwards Benjamin , Calabrese Christopher , Pagès Gilles , Pouyssegur Jacques , Vogel Peter , McGargill Maureen Ann 
Published: January 2023

Abstract
ERK1 and ERK2 are serine/threonine kinases critical for the proliferation and development of T cells. Loss of ERK signaling in T cells, mediated by conditional deletion of Erk2 (CD4Cre) on an Erk1-/- background (DKOCD4), results in a block in the thymic development of T cells. Surprisingly, 80% of DKOCD4 mice spontaneously developed visible osteochondromas by 28 weeks of age. Histological analysis of these lesions revealed excessive accumulation of hypertrophic chondrocytes originating from the growth plates, but no mononuclear infiltrate indicative of inflammation. To determine if these lesions were caused by deletion of Erk in T cells, DKOCD4 mice were bred to Rag1-/- mice. Unexpectedly, osteochondromas still appeared in DKOCD4Rag1-/- mice, indicating deletion of Erk2 in other cell types mediates excess cartilage accumulation. Moreover, the addition of T cells delayed development of osteochondromas, which is a previously unknown level of regulation in cartilage homeostasis. Osteochondromas also appear to be influenced by alterations in the microbiota, as DKOCD4 mice treated with an antibiotic cocktail have a delay in osteochondroma development, which can be accelerated by housing the mice in non-specific-pathogen free conditions. Together these data suggest that Erk plays a critical role in a CD4+ cell type other than T cells, possibly an innate-like lymphocyte, to alter cartilage homeostasis. Finally, we present a novel role for T cells in regulating this process.
Maintenance of immune diversity during an effector T cell response in face of antigen selection (IRC8P.444)
Authors: Devarajan Priyadharshini , Zou Tie , McKinstry Karl , Flies Amanda , Swain Susan , Dutton Richard 
Published: January 2023

Abstract
Self-antigen recognition has been shown to be instrumental for the maintenance of the pool of circulating naïve T cells. While the mechanisms of immune diversity maintenance in the naive T cell repertoire have been explored, how immune diversity is maintained in the face of antigen selection is less understood. Data from several studies show that self-peptide presented by FRCs in the secondary lymphoid organs help maintain the diversity of the naïve T cell repertoire. We propose that an analogous mechanism is in play even during the effector stage of an immune response, which if left unchecked would bias the repertoire towards clones with higher affinity for the foreign antigen. In this study, we report a clone-specific regulation of the diversity in the face of antigen selection. Our data show that CD8+ T cell clones selected on the same self peptide compete for this self-antigen presented by stromal cells even during the clonal expansion phase in an effector response. The supply of self-peptide and hence IL-7 becomes limiting as the clone increases in size and the ability for the clone to further expand is curtailed. Such a mechanism would explain the maintenance of the diversity of the immune repertoire even through an antigen-driven response as T cells transition from being naïve to effectors.
CCR7 modulate the homeostasis of CD8 T cells in response to acute viral infections (IRC8P.445)
Authors: Jung Yong 
Published: January 2023

Abstract
CCR7 is an important chemokine receptor for naive and memory T cells to migrate toward T cell zone of the spleen and lymph nodes where CCL19 and CCL21 are expressed. Although the role of this receptor in the antigen-dependent activation of T cells is well documented, it is still not clear if CCR7 alters the homoestasis of effector and memory T cells during acute viral infections. Here, we report that the deficient of CCR7 expression increased the number of memory CD8 T cells particulary in the lung and bone marrow compared to CCR7 wild-type T cells following LCMV infections. We also demonstrated that CCR7-deficient memory T cells proliferated homeostatically faster than wild type controls. This is presumably a result of increased exposure to IL-15 as an outcome of diminished experience of IL-7 because the numbers of CCR7-deficeint and CCR7-sufficient memory T cells are comarable in IL-15 knock-out mice but not in IL-7 deficient mice. Therefore, IL-15 is suggested to be the dominant factor for the increased homeostasis of CCR7 deficient memory T cell pool. Based on these data, we concluded that CCR7 predispositions memory CD8 T cells into the IL-7-dependent niches rather than IL-15- and this also offers better understandings of the regulation of homeostasis based on the differential CCR7 expressions of memory T cell subsets.
Hyperproduction of IL-6 caused by aberrant TDP-43 overexpression in high-fat diet-Induced obese mice (IRM9P.602)
Authors: Kang Sujin , Lee Sungwook , Park Boyoun 
Published: January 2023

Abstract
Inclusion of Tat-activating regulatory DNA-binding protein-43 (TDP-43) due to hyperphosphorylation or hyperubiquitination is one of the main causes of neurodegenerative diseases. In particular, cellular TDP-43 expression levels are tightly controlled through a negative feedback loop involving its mRNA; however, misregulation of TDP-43 expression is linked to neuropathology. Very recently, we reported that the TDP-43-mediated subnuclear body is an essential site of interleukin -6 (IL-6) pre-mRNA processing. Here, we show that aberrant TDP-43 overexpression is significantly associated with the pathogenesis of obesity. Mice fed a high-fat diet exhibit increased TDP-43 expression in the liver and fat-pad masses along with a prominent increase of IL-6 production. Importantly, overexpression or depletion of TDP-43 significantly increases or decreases, respectively, IL-6 pre-mRNA processing and mRNA production in adipose cells. Furthermore, in vivo depletion of TDP-43 reduces IL-6 production in the liver. Thus, our findings provide evidence that homeostasis of TDP-43 expression influences IL-6 production levels, and thus, the alteration of IL-6 levels by disruption of TDP-43 self-regulation causes a high risk of developing obesity.
ATF4 reprograms T cell metabolism in response to the environmental stress and is required for Th1 immune responses (IRM9P.459)
Authors: Xia Rui , Lu Binfeng , Yang Xi 
Published: January 2023

Abstract
Rui Xia1, Xi Yang1, 3, Binfeng Lu1, 2 1 Department of Immunology, School of Medicine, University of Pittsburgh, EBST E1047, 200 Lothrop Street, Pittsburgh PA 15261, USA. 2 University of Pittsburgh Cancer Institute 3 School of Medicine, Tsinghua University, HaiDian, Beijing P.R. China 100084 Abstract: T cell metabolism is strongly influenced by the extracellular tissue microenvironment such as oxidizing status and amino acid availability. The underlying molecular mechanisms are not well understood. Here, we showed that increased extracellular oxidation and amino acid starvation induced a unique ATF4-regulated genetic program in T cells. ATF4 deficient T cells had a severe defect in metabolism, particularly in the oxidizing as well as amino acid-deprived environments. Lack of ATF4 resulted in T cell autonomous defects in the function of Th1 cells. In vivo, ATF4 deficiency resulted in decreased antitumor immune responses and associated with drastic changes of the tumor microenvironment. Our study establishes that ATF4 plays an important role in T cell metabolism and is important for the Th1 type immune response.
Mesenchymal stromal cell immunomodulation and aryl hydrocarbon receptor activation by tryptophan catabolites (IRM9P.462)
Authors: Lewis Christopher , Chinnadurai Raghavan , Galipeau Jacques 
Published: January 2023

Abstract
The catabolism of Trp by indoleamine 2,3-dioxygenase (IDO) is a key correlate of the immunomodulation by human mesenchymal stromal cells (MSCs). AHR is a cytosolic protein expressed by a variety of cells, that upon activation, initiates transcription at aryl hydrocarbon response elements (AHREs). We show MSCs express AHR basally, and hypothesized that the catalytic activity of IDO and signal transduction via AHR are linked, as intracellular signals which deploy MSC suppressive properties. To test this, we treated MSCs with hydrocarbons known to activate AHR: TCDD or FICZ. Upon treatment of resting MSCs with TCDD or FICZ, we observed 100-fold induction of Cyp1a1/1b1 mRNA, reflective of AHRE activation. We next examined the response of MSCs after 48h treatment with 1MT, Trp, kynurenine (Kyn) or kynurenic acid (KynAc), the latter two being IDO-catalyzed Trp metabolites. We observed 1MT and KynAc both induced Cyp1a1/1b1 expression by 60-fold. These data support the theory that IDO-catabolism of Trp generates endogenous ligands (i.e.KynAc) which can directly activate AHR. We performed T cell suppression assays, and observed Trp catabolites augment the immunosuppressive function of MSCs (independently of PDL1 or IDO). Our findings suggest endogenous AHR signals from IDO catalysis may play a role in MSC immunomodulation. This observation supports a novel paradigm for intracellular signaling from catabolic conversion of Trp to AHR ligands and induction of immunomodulatory properties.
Histone deacetylase inhibitors dampen antibody and autoantibody responses by upregulating selected B cell microRNAs that silence AID and Blimp-1 expression (IRM10P.603)
Authors: Zan Hong , White Clayton , Pone Egest , Lam Tonika , Tat Connie , Li Guideng , Casali Paolo 
Published: January 2023

Abstract
Class-switch DNA recombination (CSR) and somatic hypermutation (SHM), which require AID, and plasma cell differentiation, which requires Blimp-1, are critical for the generation of class-switched and hypermutated (mature) antibody and autoantibody responses. We show that histone deacetylase inhibitors (HDIs) valproic acid (VPA) and butyrate upregulated miR-155, miR-181b and miR-361 to silence AICDA/Aicda, and miR-23b, miR-30a and miR-125b to silence PRDM1/Prdm1, in human and mouse B cells. This led to downregulation of AID, Blimp-1 and Xbp-1, thereby inhibiting CSR, SHM and plasma cell differentiation. The selectivity of HDI-mediated silencing of AICDA/Aicda and PRDM1/Prdm1 was emphasized by unchanged expression of HoxC4 and Irf4 (important AICDA/Aicda inducer/modulators), Rev1 and Ung (central elements for CSR/SHM), and Bcl6, Bach2 or Pax5 (repressors of PRDM1/Prdm1 expression), as well as unchanged expression of miR-19a/b, miR-20a and miR-25, which are not known to regulate AICDA/Aicda or PRDM1/Prdm1. Through these B cell intrinsic epigenetic mechanisms, VPA blunted class-switched and hypermutated T-dependent and T-independent antibody responses in C57BL/6 mice. It also decreased class-switched and hypermutated autoantibodies, ameliorated disease and extended survival in lupus MRL/Faslpr/lpr mice. Our findings outline important epigenetic mechanisms of modulation of antibody responses and providing proof-of-principle therapeutics in autoantibody-mediated autoimmunity.
Novel role of B cell receptor signaling in regulation of Tcl1, an oncogene, and Par-4, a tumor suppressor gene, in B cell chronic lymphocytic leukemia (IRM10P.619)
Authors: McKenna Mary , Nooti Sunil , Alhakeem Sara , Gachuki Beth , Byrd John , Muthusamy Natarajan , Rangnekar Vivek , Bondada Subbarao 
Published: January 2023

Abstract
B cell malignancies such as non-Hodgkin’s Lymphoma have a probability of affecting 1 in 43 people in the United States, contributing to 7% of all cancer related deaths. The most aggressive forms of non-Hodgkin’s Lymphomas, which include Chronic Lymphocytic Leukemia (CLL), express elevated levels of T cell leukemia 1 (Tcl1), an oncogene that promotes cell survival. CLL is characterized by clonally expanded population of CD5+CD19+ B lymphocytes with impaired apoptotic mechanisms. The Eµ-Tcl1 mouse, serves as an excellent model for the development of CLL due to Tcl1 overexpression in B cells through the Ig VH promoter and Eµ enhancer. In these CLL cells the B-cell receptor (BCR) signaling pathway is activated as shown by constitutive tyrosine phosphorylation of the Src Family Kinases (SFK) and total expression of Lyn, compared to normal B cells. Treatment of B-CLL cells with dasatinib, an SFK inhibitor, results in decreased proliferation and cell death, a decrease in Tcl1, and surprisingly, a decrease in prostate apoptosis response-4 (Par-4), a pro-apoptotic protein. Knockdown of Lyn with shRNA in B-lymphoma cells, also reduced Par-4 suggesting a specific role of Lyn in Par-4 regulation. Par-4 was also downregulated after inhibition of other non-receptor tyrosine kinases such as Syk and Btk involved in BCR signaling. Presently, we are determining the importance of Par-4 in the growth of B-CLL and the mechanism of novel regulation of Par-4 and Tcl1 through BCR signaling.
T-bet regulates long-lived plasma cell development in an influenza model (IRM10P.604)
Authors: Stone Sara , Ballesteros-Tato Andre , Lund Frances 
Published: January 2023

Abstract
Long-lived plasma cells (LLPC) arise from germinal center B cells (GCB). The transcription factor Bcl6, which is required for GCB cell survival, inhibits LLPC development by repressing the transcription factor Blimp1, which normally initiates LLPC development. To date, it is not clear how these opposing transcription factors are regulated in GCB cells. In T lymphocytes, the transcription factor T-bet modulates the balance between Blimp1 and Bcl6 and controls the subsequent differentiation of the T cells into memory and effector cells. When naïve B cells are activated in vitro with T helper 1 (Th1) cells, the B cells differentiate into antibody (Ab) secreting cells in a T-bet and IFNγ dependent manner. Therefore, we hypothesized that B cell intrinsic expression of T-bet would also be necessary for LLPC development following influenza A infection. We found that T-bet expression increased in GCB cells formed after flu infection and was highest within GCB cells expressing low levels of the PC marker CD138, suggesting that T-bet supports PC differentiation from GCB cells. In chimeric mice in which 50% of cells are T-bet-/-, T-bet-/- GCB cells expressed lower levels of Blimp1 and IRF4 than WT GCB cells. Furthermore, flu-specific Ab titers were attenuated in chimeric animals lacking T-bet selectively within the B lineage cells compared to control chimeras with WT B cells. These results support a role for T-bet in the development of LLPC following influenza infection.
Notch1 is an important secondary stimulator for activated B cells (IRM10P.606)
Authors: Park Sung-Gyoo , Park San-Heon , Kang Jung-Ah 
Published: January 2023

Abstract
The roles of Notch1 and Notch2 in T cell function have been well studied, but the functional roles of Notch in B cells have not been extensively investigated, except for Notch2 involvement in peripheral marginal zone B cell differentiation. This study examined the roles of Notch1 in murine primary B cells. We found that the intracellular domain of Notch1 could substitute for Notch2 in marginal zone B cell differentiation, and that Notch1 expression was important for further activation of B cells. During B cell activation by B cell receptor ligation, Notch1 was up-regulated while Notch2 was not. In addition, Notch1 up-regulation itself did not contribute to the further activation of B cells, but the Notch ligand was important for Notch1-mediated further B cell activation. Moreover, Notch1 increased antibody secretion from activated B cells. These data suggest that Notch1 is more important for B cell activation than Notch2, while Notch2 is more important for marginal zone B cell differentiation.
Regulation of IgM+ memory B cells by the inhibitory FγRIIb (IRM10P.610)
Authors: Papillion Amber , Winslow Gary 
Published: January 2023

Abstract
Our laboratory has described a long-term IgM+ memory population in the spleens of mice infected with Ehrlichia muris (J. Immunol. 191:1240). Among the many surface markers that distinguish the memory cells from conventional B cells is the inhibitory receptor FcγRIIb, which exhibited 4-fold higher expression. We hypothesized FcγRIIb negatively regulates IgM+ memory cells by binding immune complexes present during low-level chronic infection. To investigate this question, we monitored the population in infected FcγRIIb-deficient mice. Thirty days post-infection, the IgM+ memory B cells were increased by 3-fold in frequency in FcγRIIb-deficient mice, compared to control mice. This increase in the frequency of spleen IgM+ memory cells was due to an increase in the number of IgM+ memory cells, and not simply a decrease in the number of other B cells present. Preliminary studies revealed the IgM+ memory population generated in FcγRIIb-deficient mice was identical in phenotype to IgM+ memory cells generated in infected wild-type mice. The increase in the IgM+ memory population was associated with an increase in antigen-specific IgG. These data indicate that FcγRIIb plays an important role in regulating the expansion and/or persistence of IgM+ memory cells. We propose the inhibitory receptor acts to limit the contribution of IgM+ memory cells to recall responses under conditions where antigen-specific IgG is sufficient to control infection.
ICOSL-mediated signaling is essential for the survival and functional maturation of germinal center B cells through the classical NF-κB pathway (IRM10P.611)
Authors: Zheng Biao , Xu Guiliang , Chen Xi , Marinova Ekaterina , Han Shuhua 
Published: January 2023

Abstract
The molecular mechanisms by which helper T-cells support B-cell activation, survival and functional differentiation in the germinal center (GC) are not well-defined. To date, signaling through CD40 by CD40L is the only established receptor-ligand signaling pathway initiated by helper T-cells. Here we show that helper T-cells provide helper signal to B-cells through the inducible T-cell co-stimulator (ICOS)-ICOS ligand (ICOSL) interaction. We found that reverse ICOSL signaling on GC B-cells is essential and sufficient to promote GC B-cell survival and functional maturation; whereas CD40-mediated signaling plays a minor role during GC reaction, although critical in initiating the GC response. In vivo ICOSL engagement by ICOS-Ig fusion protein can rescue impaired GC formation and antibody production in ICOS-deficient mice. Various lines of ICOSL mutant mice, including pan-B cell-specific ICOSL-deficient mice, GC B cell-specific ICOSL-deficient mice, and ICOSL intra-cellular domain mutant mice, all show defective humoral response and impaired GC reaction. ICOSL reverse signaling in GC B cells is dependent on activation of the classical NF-kB signal pathway, resulting in increased BCL2, c-MYC and FOXO1 expression that supports GC B cell survival and differentiation. Thus, CD40-CD40L interaction mainly supports the initiation of GC response, whereas ICOS-ICOSL collaboration provides bi-directional signals that support the maintenance and functional maturation of GC B cells.
Boosting antitumor immunity through TIM1 (IRM11P.631)
Authors: chen xiaojuan , Wang Xuefeng , Lu Binfeng 
Published: January 2023

Abstract
The lack of co-stimulation, as well as the dominance of co-inhibition, of type 1 lymphocytes, such as CD8+ T cells and NK cells, is a principal immunosuppressive mechanism in the tumor microenvironment. Conversion of the tumor immunosuppressive microenvironment to one that favors cancer-eradicating immune responses is therefore a goal for the development of more effective cancer immunotherapy. Targeting co-stimulatory pathways represents one attractive therapeutic strategy. T cell Ig mucin (TIM) proteins are structurally related to type I membrane glycoproteins. Previous studies have shown that TIM-1 is highly expressed on activated CD4+ T cells, facilitates the activation of Th1 cells, Th17 cells, and Th2 cells, and is implicated in the pathogenesis of human allergy and autoimmune diseases. These data support an important role for TIM-1 in regulating CD4+ T cell function. However, the role for TIM-1 in CD8+ T cell- or NK cell-mediated immune responses, including antitumor immune responses, is unknown. Here we showed that tumoral expression of antitumor cytokines such as IL-12 and IL-33 upregulated TIM-1 on tumor-infiltrating CD8+ T cells and NK cells. In addition, we demonstrated that TIM1 mAbs greatly inhibited tumor growth, resulting in greatly elevated cellular immune responses against tumor. The in-depth mechanistic insights and implication in tumor immunity are gained by our studies. Our study establishes TIM-1 as a potential target for enhancing antitumor immunity.
Sodium arsenic and ultraviolet-radiation synergistically induce cell injury in lens and retinal epithelial cells occurring migration of HMGB1 (IRM11P.639)
Authors: Park SuJung , Shin Jeon-Soo 
Published: January 2023

Abstract
Although sodium arsenic (As) and ultraviolet radiation (UVR) can induce cell injury through either DNA damage or reactive oxidative species (ROS) in various epithelial cells, whether damaged-associated molecular pattern (DAMP) involved in cell injury is still unclear. To determine the association of HMGB1, one of DAMP molecules that can be secreted by oxidative stress, we investigated cell injury in human lens epithelial cell (HLE B3) and human retinal epithelial cell (ARPE-19) using cell viability assay, western blot, confocal microscopy and flow cytometry (FACS analysis). In both HLE B3 and ARPE-19 cells, DNA damage marker, cleaved PARP and cell viability assay showed that UVR synergistically increased As-caused cell death(injury). During UVR and As-caused cell injury, HMGB1 was translocated from nucleus to cytosol and then secreted to extracellular region. ROS scavenger N-acetylcystein (NAC) and mito-tempo inhibited both translocation and secretion of HMGB1 in dose-dependent manner, implicating that migration of HMGB1 is closely associated with ROS generation in mitochondria. Taken together, we concluded that HMGB1 is associated in cell injury caused by UVR and As. Nevertheless how migrated HMGB1 plays a role in UVR-As caused cell injury of HLE B3 and arpe-19 cells is still unclear.
TLR9 plays a critical role in sepsis-induced inflammatory response (IRM11P.623)
Authors: Yin Deling , Denney James , Yan Hui , Hu Dan , Caudle Yi , Li Hui 
Published: January 2023

Abstract
Sepsis, a major clinical problem with high morbidity and mortality, is caused by overwhelming systemic host-inflammatory response. Toll-like receptors (TLRs) play a fundamental role in induction of hyperinflammation and tissue damage in sepsis. In this study, we demonstrate a protective role of TLR9 inhibition against the dysregulated inflammatory response and tissue injury in sepsis. TLR9 deficiency decreased the mortality of mice following cecal ligation and puncture (CLP) -induced sepsis. TLR9 knockout mice showed dampened p38 activation and augmented Akt phosphorylation in the spleen, lung and liver. In addition, TLR9 deficiency decreased the levels of inflammatory cytokines and attenuated splenic apoptosis after CLP. These results indicate that TLR9 inhibition might offer a novel therapeutic strategy for the management of sepsis.