bluuebunny/crossref_metadata_2025_split huggingface dataset:
High endothelial venules at the nexus of an IL-6/gp130/STAT3 axis controlling immune surveillance during fever (173.22)
Authors: Vardam Trupti , Appenheimer Michelle , Zhou Lei , Chen Qing , Wang Wan-Chao , Ernst Matthias , Rose-John Stefan , Baumann Heinz , Evans Sharon 
Published: January 2023

Abstract
Fever remains the least understood component of acute inflammation although it confers a survival benefit in endothermic and ectothermic vertebrates. Here we show that LPS- or turpentine-induced fever enhances immune surveillance by augmenting lymphocyte trafficking via high endothelial venules (HEV) in lymph nodes. We identified an autocrine feed-forward loop during the effector phase of fever in which IL-6 produced by HEV acts via the gp130 signal transducing subunit of the IL-6 receptor to enhance ICAM-1-dependent lymphocyte trafficking. Comparative analysis of the thermal response in gp130Y757F and gp130ΔSTAT mutant mice implicated STAT3/1 in the pathway downstream of fever that controls lymphocyte trafficking. An obligate role for STAT3 signaling was further delineated using Stat1-/- mice. While gp130-dependent MEK1-ERK1/2 signaling was not required for enhanced lymphocyte trafficking, ERK1/2 activation was necessary for the metalloproteinase-dependent shedding mechanism that restores endothelial ICAM-1 to homeostatic levels during the resolution phase of inflammation. Finally, thermally-induced lymphocyte trafficking across HEV lowered the threshold for antigen-driven priming of naïve T cells in lymph nodes. Taken together, these studies provide insight into a novel IL-6/gp130/STAT3 axis that acts as a highly integrated thermally-sensitive alert system to heighten immune surveillance during febrile responses.
The E3 ubiquitin ligase TRIM21 forms a complex with p62 and TRAF6 and promotes degradation of TRAF6 (P1176)
Authors: Yoshimi Ryusuke , Watanabe Reikou , Tsukahara Toshinori , Hama Maasa , Ihata Atsushi , Ueda Atsuhisa , Takeno Mitsuhiro , Morse III Herbert , Ozato Keiko , Ishigatsubo Yoshiaki 
Published: January 2023

Abstract
NF-κB signaling pathway plays a pivotal role in inflammatory response, and its excessive activation causes systemic inflammatory disorder, such as systemic lupus erythematosus (SLE). TRIM21, one of the tripartite motif (TRIM) family members, is an E3 ubiquitin ligase that functions in both innate and acquired immunity. It is also an autoantigen known as Ro52/SS-A, which is observed in patients with SLE. Recent studies, including Trim21 gene disruption studies, suggest that TRIM21 is a negative regulator for NF-κB-dependent proinflammatory cytokine production. However, the molecular mechanism still remains to be clarified. Here we report that TRIM21 interacted with tumor necrosis factor-associated factor 6 (TRAF6), an essential adaptor protein for Toll-like receptor/interleukin 1 receptor (TLR/IL-1R)-mediated activation of NF-κB signaling pathway. The TRIM21-TRAF6 interaction was indirect and mediated by a scaffold protein, p62/sequestosome 1. TRIM21-overexpressed fibroblast cell line showed decreased expression of TRAF6 as compared to the control cells. TRIM21 promoted not only K63-linked ubiquitylation but also K48-linked ubiquitylation of TRAF6 in the presence of p62. Furthermore proteasome inhibitor MG132 increased the ubiquitylated TRAF6 proteins. These data suggest that the function of TRIM21 as a negative regulator for NF-κB signaling is attributed to the proteasome-mediated degradation of TRAF6.
Induction of expression of LAT1, an essential amino acid transporter, in activated T cells (P1182)
Authors: Hayashi Keitaro , Endou Hitoshi , Anzai Naohiko 
Published: January 2023

Abstract
Activation of T cell accompanies remarkable enhancement of metabolism. Sufficient and continuous supply of nutrient such as amino acid is thus considerable importance to support immune reaction in T cell. However, the molecular mechanism of efficient incorporation of amino acid into activated T cell has not been determined. We characterized LAT1 as an essential amino acid transporter which is highly expressed in activated T cell. TCR stimulation and co-stimulation of human T cell triggered the dramatic induction of LAT1, although neither TCR stimulation nor co-stimulation alone did not affect the LAT1 expression. The promotion of LAT1 expression in activated T cell was prohibited by inhibitor of NF-kB and AP-1. These results indicate that LAT1 expression is induced by full activation of T cell and LAT1 could work as a potential transporter for essential amino acid in activated T cell. Our result that NF-kB and AP-1 are essential for LAT1 expression suggests that nutrient supply system and immune reaction system are included in one program and those systems are activated by the same molecular machinery in T cell.
Defining the roles of calcium mobilization in the initial decondensation of chromatin during T cell activation (P1162)
Authors: Rawlings Jason , Bingham Kellie , Lee Megan , Wooten Sam 
Published: January 2023

Abstract
Condensation of chromatin within the nucleus of T lymphocytes occurs during thymocyte development and is a requirement for proper T cell development and maintenance of the naïve (quiescent) state. T cell activation via stimulation of the T cell receptor (TCR) is a necessary step in an immune response, allowing T cells to gain the ability to proliferate in response to cytokines, such as IL-2. During this activation process, the chromatin within T cells decondenses, allowing access to the previously inaccessible DNA, permitting the transcription of genes required for proliferation. We demonstrate that stimulation of either the IP¬3 (inositol triphosphate) or DAG (diacylglycerol) pathways downstream of the TCR leads to chromatin decondensation, but with different kinetics. Within the IP3 pathway, we show that extracellular calcium is not required for the initial decondensation of chromatin. Furthermore, we show that the release of calcium from intracellular stores is sufficient and required for the initial decondensation of chromatin following TCR engagement. Interestingly, while calcium mobilization results in a decondensation of chromatin, it is not sufficient for STAT5 target gene expression. However, chromatin decondensation via the DAG pathway is capable of making T cells competent to respond to IL-2. These findings suggest that there may be at least two distinct domains of condensed chromatin in naïve T cells.
IL17A and IFNγ jointly control rapidly fatal eosinophilic myocarditis in mice (P4120)
Authors: Barin Jobert , Baldeviano G. , Talor Monica , Wu Lei , Ong SuFey , Fairweather DeLisa , Bedja Djahida , Stickel Natalie , LeGault Jillian , Cardamone Ashley , Zheng Dongfeng , Gabrielson Kathleen , Rose Noel , Cihakova Daniela 
Published: January 2023

Abstract
Deviation to autoaggressive T helper 17 (Th17) responses has been reported to account for the protective effect of interferon-gamma (IFNγ) in certain animal models of autoimmune disease. Building on our previous findings that interleukin-17 (IL17) signaling is critical for the progression of experimental autoimmune myocarditis (EAM) to dilative heart failure, we sought to address the question of whether IL17 mediated the severe form of EAM observed in IFNγ-deficient mice. To our surprise, we found that IFNγ-/-IL17A-/- double-knockout (DKO) mice had greater mortality compared to IFNγ-/- mice, starting at day 14 and reaching 50% by day 21 of EAM. DKO hearts were severely infiltrated, indicating acute inflammatory heart failure as the mode of death in these mice. We found pronounced eosinophilic infiltration in DKO mice, implicating eosinophils as mediators of the enhanced morbidity. Cardiac production of CCL11/eotaxin was increased, alongside Th2 deviation among heart-infiltrating CD4+ T cells. Intriguingly, blockade of IL4 in IFNγ-/-IL17A-/-DKO mice inhibited Th2 deviation, but failed to resolve eosinophilia or morbidity. However, developmental ablation of eosinophils partly rescued the survival of DKO mice. These data point to a novel collaboration between IFNγ and IL17A in controlling eosinophil recruitment.
Pre-conditioning with high-mobility group box 1 (HMGB1) attenuates excessive TLR-mediated inflammation. (INM9P.456)
Authors: Lim A Ram , Kim Sol , Park Su Jung , Shin Jeon soo 
Published: January 2023

Abstract
Activation of innate immunity via TLRs plays a pivotal role in host defense against pathogens through the recognition of PAMPs. However, since uncontrolled immune response leads to various kinds of autoimmune and inflammatory diseases, TLR signaling should be tightly regulated. Recent studies have shown that HMGB1 could be critical for the control of TLR signaling. In this study, we demonstrated that HMGB1 mediated negative regulating signals of TLR activation. Our data indicated that HMGB1 induced NF-κB activation via non-canonical pathway by processing of p100 to p52 and translocation of p52 into the nucleus. Also, HMGB1 induced expression of TRIM30α which is a regulator of TLR signaling. Preconditioned HMGB1 attenuated TLR activation by LPS in murine, human macrophage cell lines and mouse BMDM. Treatment of HMGB1 followed by LPS stimulation decreased TNF-α and IL-6 level in mouse BMDM when compared with LPS stimulation alone. Furthermore, HMGB1 pretreatment in the presence of polymyxin B, an endotoxin inactivator, induced HMGB1-mediated tolerance. Pretreatment of HMGB1 promoted rapid termination of signaling in macrophage cells through transcription factor NF-κB by augmenting negative regulators of TLRs such as TRIM30α and SHIP-1. Knockdown experiments using TRIM30α-specific small interfering RNA impaired the HMGB1-mediated TLR tolerance. Collectively, our results demonstrate that HMGB1 mediated the mechanism for prevention of excessive TLR-mediated inflammation.
Characterizing the role of Blimp-1 in regulating encephalitogenic T cells in CNS autoimmunity (IRC8P.483)
Authors: Nuro-Gyina Patrick , Liu Yue , Pei Wei , Larson Michelle , Lovett-Racke Amy , Racke Michael , Yang Yuhong 
Published: January 2023

Abstract
Effector and recall responses of T cells play an important role in the pathogenesis of Multiple Sclerosis and EAE. B lymphocyte induced maturation protein-1 (Blimp-1) is a transcription factor that plays important roles in regulating immunity. However, its role in regulating encephalitogenic T cells in EAE has not been characterized. Using YFP/Blimp-1 reporter mice, we analyzed Blimp-1 expression in myelin-specific CD4 T cells in vitro and in vivo. Blimp-1 expression correlates with the encephalitogenicity of myelin-specific CD4 T cells, which is highly expressed in encephalitogenic Th1 and Th17 cells, but not in non-encephalitogenic Th17 cells. Moreover, Blimp-1 is highly expressed in myelin-specific CD4 T cells in the draining lymph nodes, spleen and CNS during EAE development, specifically in activated CD44+IL7Rα+CD4 T cells. As IL-23 significantly enhances the encephalitogenicity of myelin-specific CD4 T cells, we determined if IL-23 upregulates Blimp-1 expression. Our data showed that exogenous IL-23 significantly enhances Blimp-1 expression in myelin-specific CD4 T cells and Blimp-1 is highly expressed in IFNγ+, IL-17+ and IFNγ+ and IL-17 double positive cells in draining LN cells, splenocytes and CNS infiltrating cells. In addition, we determined the role of Blimp-1 in regulating T cell migration and EAE development. Together, our findings suggest that Blimp-1 might play an important role in regulating autoreactive T cells and the development of CNS autoimmunity.
Heme oxygenase-1/CO protect against post-traumatic suppression of adaptive immune responses (IRC8P.475)
Authors: Darwiche Sophie , Wang Yanting , Brumfield John , Stratimirovic Sladjana , Vreeland Kathryn , Botero Ana , Martinez Sylvia , Escobar Daniel , Luciano Jason , Kautza Ben , Zuckerbraun Brian 
Published: January 2023

Abstract
Traumatic injury induces a systemic dysregulated immuno-inflammatory response that contributes to mortality. This response includes an upregulation of pro-inflammatory cytokines by innate cells and an independent suppression of adaptive immunity characterized by reduced Th1 responses. Heme oxygenase-1 (HO-1) and its byproduct, carbon monoxide (CO), are protective against injury-induced inflammation and end-organ damage, but their beneficial role in the dysregulation of adaptive responses following trauma is unknown. To investigate this, B6 mice received multiple-trauma or no manipulation, and were given either vehicle or a HO-1 inducer (Cobalt protoporphyrin, CoPP; 5mg/kg) prior to injury. Another cohort received either room air or CO (250ppm) for 4 hours directly post-injury. At 48hr post-trauma, Tcell functions were assessed by ex-vivo mitogen-induced Tcell proliferation and Th1 cytokine release (IL-2 and IFN-γ). As expected after injury, a near 50% reduction in Tcell proliferation was seen in vehicle- or air-treated trauma mice, compared to uninjured controls (p=0.007). A parallel reduction in Tcell IL-2 and IFN-γ release was observed. In clear contrast, CoPP or CO treatment prevented trauma-induced reductions in Tcell proliferation and cytokine release (fold difference 0.90±0.10 and 1.21±0.16 to uninjured controls, respectively). Overall, HO-1 represents an endogenous protective pathway that can be exploited following trauma to preserve normal immune functions & survival.
Manipulating number and function of effector CD8 T cells (IRC9P.710)
Authors: Kim Marie , Harty John 
Published: January 2023

Abstract
In response to infection or vaccination, CD8 T cells undergo massive proliferative expansion in numbers followed by a contraction phase where 90-95% of the expanded population is eliminated through apoptosis, with the remaining cells initiating the memory pool. Although basic CD8 T cell kinetics in response to infection and immunization have been described, the mechanisms regulating how memory CD8 T cell numbers are determined remain unknown. The current paradigm regarding memory CD8 T cell numbers states that the size of the memory pool is dictated primarily by the peak numbers achieved after infection or immunization. However, our data directly challenge this paradigm. Here, we demonstrate that DC-immunization and infection models, coupled with stimulatory IL-2/Ab complex treatment, can increase peak effector CD8 T cell numbers over 100-fold with no concurrent increase in memory CD8 T cell numbers post-contraction. Additionally, IL-2/Ab complex treatment not only increases effector CD8 T cell numbers, but also enhances and sustains expression of cytolytic molecules such as granzyme B, 4-1BB, and GITR. Thus, our data dissociate the magnitude of effector CD8 T cell expansion from memory set point, as well as highlight how IL-2/Ab complexes can enhance effector CD8 T cell function. Our findings suggest that IL-2/Ab complex therapy may be useful in short-term elevation of effector CD8 T cell numbers and function for tumor immunotherapy or during infectious disease outbreaks.
Altered CD8 T cell memory development in the presence of bystander chronic infections and inflammation (IRC9P.712)
Authors: Stelekati Erietta , Shin Haina , Doering Travis , Dolfi Douglas , Ziegler Carly , Beiting Daniel , Dawson Lucas , Liboon Jennifer , Wolski David , Ali Mohammed-Alkhatim , Katsikis Peter , Shen Hao , Roos David , Haining W. , Lauer Georg , Wherry John 
Published: January 2023

Abstract
Chronic infections impair immune responses to unrelated pathogens and vaccines but the underlying mechanisms are not clear. We investigated whether bystander chronic infections impact the differentiation of memory CD8 T cells. We demonstrate that diverse chronic viral and parasitic infections substantially impair both the quantity and quality of developing memory CD8 T cells, independently of initial priming. Fully-formed memory CD8 T cells were less susceptible, though not impervious, to the effects of bystander chronic infection, suggesting that the impact of inflammation on memory development is more prominent during the critical period of transitioning from effector to memory. Prolonged induction of type I IFN recapitulated the effects of chronic bystander infection on memory CD8 T cell development, though these effects were independent of IFNAR signaling on the CD8 T cells during chronic infection. However, systemic blockade of IFNAR signaling after the priming phase enhanced the survival and the numerical seeding of the developing memory CD8 T cell pool. In contrast to survival, altered CD8 T cell memory differentiation was regulated by the transcription factors Tbx21 (T-bet) and Prdm1 (Blimp-1), specifically in the post-effector phase. Thus, exposure to chronic bystander infections and inflammation impairs the transition from effector to memory. These results have relevance for immunity and vaccination during persisting infections and chronic inflammation.
Human IL-7Rα low memory CD8+ T cells are clonal anergic cells being reversed by exogenous IL-2 (IRC10P.469)
Authors: Sim Ji Hyun , Cho Bon-A , Lee Sunkyung , Ko Youngho , Seol Min A , Kim Jin-Hee , Oh Keunhee , Lee Dong-Sup , Kang Insoo , Choi Kyung-Ho , Kim Hang-Rae 
Published: January 2023

Abstract
We have found two subsets of CD8+ T cells expressing IL-7Rα high and IL-7Rα low with different cell survival responses to IL-7 in peripheral blood of human. Of interest, these IL-7Rα low memory CD8+ T cells that comparably express effector molecules have impaired proliferation and IL-2 production upon TCR stimulation by anti-CD3/CD28 Abs. Treating IL-7Rα low memory CD8+ T cells with anti-CD3/CD28 Abs did not produce IL-2, but comparably expressed IFN-γ and TNF-α, as shown in split anergic cells. Importantly, IL-7Rα low memory CD8+ T cells have reduced calcium flux and subsequent inhibited nuclear translocation of NF-AT1 upon in vitro TCR stimulation by anti-CD3/CD28 Abs, leading to impaired IL-2 production. Moreover, inhibition of IL-2 production and proliferation was not recovered by PMA/ionomycin treatment, suggesting that IL-7Rα low memory CD8+ T cells also have TCR-distal signaling defect of TCR signaling. Interestingly, this anergic status was reversed by exogenous IL-2 stimulation for 10 days, clearly distinct from adaptive tolerance induced by soluble peptide Ag. In conclusion, we firstly showed that specific subset of human CD8+ T cells, IL-7Rα low memory CD8+ T cells, are T-cell clonal anergy in vivo. Based on these findings, we are going to further investigate which mechanisms are in volved in anergic phenotype of human anergic IL-7Rα low memory CD8+ T cells, and eventually, what is the role of these cells in vivo using by humanized mouse.
Increased expression of costimulatory molecules on synovial monocytes affecting inflammatory T-cell responses in rheumatoid arthritis (RA) (IRC10P.470)
Authors: Lee Won-Woo , Hwang Yuri , Yoon BoRuem , Lee Hyunju 
Published: January 2023

Abstract
Monocytes function as crucial innate effectors during inflammation. Human monocytes can be divided into three distinct subsets based on CD14 and CD16 expression. Accumulating evidences suggest that three monocyte subsets have distinct functions in inflammatory response. We investigated the characteristics of monocytes in synovial fluid (SF) of RA patients. CD16 expression on CD14++ monocytes in the SF was significantly increased compared with that in the peripheral blood (PB) of RA patients and healthy control (HC). Microarray data showed that 3,134 genes were differentially expressed in SF monocytes compared with PB monocytes. Among the genes, CD80 and CD276 expression were significantly elevated on SF monocytes, while PB monocytes of RA and HC did not express both of them without stimulation. CD80 and CD276 belong to the B7 family, which plays a checkpoint role for modulating T-cell responses. To explore how SF monocytes gain unique properties, PB monocytes were stimulated with various cytokines and TLR ligands. TGF-β was a potent inducer of CD16 expression on monocytes, whereas expressions of CD80 and CD276 were markedly elevated by IFN-γ and GM-CSF, respectively. In vitro assay, SF monocytes were found to significantly promote Th17 and Th1 responses, compared with PB monocytes of RA patients. Our findings suggest the possible role for cytokine milieu of the SF in giving unique features to SF monocytes and their crucial roles in affecting inflammatory T-cell response in RA
The B cell response to Salmonella enteric ser. Typhimurium: promiscuous B cell recruitment for early Ab followed by extrafollicular affinity maturation (MPF6P.743)
Authors: DiNiro Roberto , Lee Seung Joo , McSorley Stephen , Shlomchik Mark 
Published: January 2023

Abstract
We have investigated the unconventional B-cell response to Salmonella typhimurium (Stm). Stm engenders a sustained IgM and IgG extrafollicular plasmablast response, with AFC numbers increasing by &gt;100-fold, but no notable germinal centers. To investigate the properties of this response, we screened large panels of plasmablast-derived mAbs for Stm specificity, using ELISA, flow cytometry, and antigen microarray. To our surprise, the majority of the response (&gt;98%) appeared to be non-specific. Polyclonal B-cell activation via TLRs was an intriguing possibility but excluded based on the identical response in MyD88-deficient mice. Conversely, BCR specificity was important, as infection of BCR transgenic mice with limited repertoire led to a &gt;10-fold loss of AFCs. We thus hypothesized that the initial response was specific, but of such low affinity that Ag-binding could not be detected. Indeed, analysis of the somatic hypermutation (SHM) pattern of specific mAb V regions suggested that SHM was necessary for detectable Ag binding. This was confirmed by reverting mAbs to germline, which caused stepwise loss of reactivity. Strikingly, laser microdissection of extrafollicular plasmablast patches demonstrated robust SHM occurring outside of GCs. These results suggest a revised vision of how clonal selection and affinity maturation operate in the response to bacteria: starting affinities are virtually undetectable, yet eventually improve by SHM occurring during the plasmablast response.
Intravital imaging shows a key role for splenic DCs in acute malaria for CD4+ T cell activation and parasite clearance (MPF6P.747)
Authors: Borges da Silva Henrique , Fonseca Raíssa , Cassado Alexandra , Salles Érika , Menezes Maria , Langhorne Jean , Marinho Claudio , Boscardin Silvia , Álvarez José , D'Império Lima Maria , Tadokoro Carlos 
Published: January 2023

Abstract
Heterogeneous populations of macrophages and dendritic cells (DCs) form a complex phagocyte network inside the red pulp (RP) of the spleen, which is a major site for the control of blood-borne infectious diseases, such as malaria. However, the dynamics of splenic DCs during Plasmodium infections are poorly understood, obscuring our knowledge about the protective role of these cells in malaria. To address this issue, the phagocytosis of infected red blood cells (iRBCs) by splenic DCs was quantified by confocal intravital microscopy, as well as by flow cytometry and immunofluorescence, in three distinct phases of blood-stage Plasmodium chabaudi malaria: at the first encounter, at pre-crisis concomitant with parasitemia growth and at crisis, when the parasitemia decline coincides with spleen closure. The in vivo and ex vivo imaging of the spleen during the early infection shows that DCs phagocytize iRBCs and interact with CD4+ T cells in CD4+ T cell-rich areas and the RP. This analysis also reveals that the RP DC population maintains the ability to phagocytize iRBCs during pre-crisis stages and greatly contributes to parasite control. These findings add novel information to the immunology field and demonstrate that in vivo imaging can help to unravel the protective mechanisms against malaria.