bluuebunny/crossref_metadata_2025_split huggingface dataset:
Curcumin protects microglia and primary cortical neurons against HIV-mediated inflammation and apoptosis (P6181)
Authors: Dong Jun , Guo Luyan , Xing Yanyan , Jiang Mingliang , Lin Liqing , Wang Junbing , Xiong Guoying 
Published: January 2023

Abstract
Curcumin is a substance in turmeric root with anti-inflammatory, antioxidant, and anti-tumor properties, and has been widely used both as an herbal drug and a food additive to treat or prevent neurodisorders. To explore whether curcumin is able to treat HIV-associated neurocognitive disorders (HAND), we treated murine microglial cell line (N9) and primary rat cortical neurons with curcumin in the presence and absence of HIV gp120 (V3 loop) protein. We found that HIV gp120 profoundly induced N9 cells to produce reactive oxygen species (ROS), tumor necrosis factor-α (TNF-α) and monocyte chemoattractant protein-1 (MCP-1). HIV-1 gp120 also induced apoptosis of primary rat cortical neurons. Curcumin exerted powerful inhibitory effect against gp120-induced neuronal damage, reducing production of ROS, TNF-α and MCP-1 by N9 cells, and inhibiting apoptosis of primary rat cortical neurons. Curcumin may exert its biological activities through inhibition of gp120-mediated rectification and transient outward potassium current, as curcumin effectively reduced gp120-mediated elevation of potassium channel current of neurons. Conclusions: HIV gp120 increases ROS, TNF-α and MCP-1 production in microglia, and induces cortical neuron apoptosis by affecting the voltage-gated potassium channel current. Curcumin protects microglia and cortical neurons against HIV-mediated inflammation and apoptosis, probably through inhibition of gp120-induced elevation of the voltage-gated potassium current.
Immune exposure to a specific sequence of antibody escape variants could program long-term potential for neutralization breadth in subtype A HIV-1 infection (P6161)
Authors: Murphy Megan , Yue Ling , Pan Ruimin , Boliar Saikat , Sethi Anurag , Tian Jianhui , Karita Etienne , Allen Susan , Cormier Emmanuel , Robinson James , Gnanakaran S. , Hunter Eric , Kong Xiang-Peng , Derdeyn Cynthia 
Published: January 2023

Abstract
Approximately one quarter of HIV-1 infected individuals will generate broadly neutralizing antibodies, but the exact mechanisms for triggering and maturation of these responses are presently undefined. We consequently investigated the roots of neutralization breadth. In a subtype A HIV-1 infected Rwandan seroconverter, we pinpointed the primary neutralizing antibody target and the successive routes of viral escape using envelope glycoproteins from the transmitted/founder virus and longitudinal escape variants along with autologous plasma and monoclonal antibodies. Initially, a single mutation at one of three clustered residues proximal to gp120’s third hypervariable loop conferred viral escape. This putative epitope subsequently elicited at least two somatically related monoclonal antibodies, which bound and neutralized the established escape mutations. Resistance to this secondary wave of immune pressure then arose in later viral envelopes through introduction of two glycans that obscured this consistently targeted space. At 16-months post-infection, what had been a narrow, regional response evolved to force recognition and neutralization of distinct envelope portions, which resulted in moderate cross-clade humoral breadth. Our data suggest that unveiling a certain chain of envelope mutations could drive B cells toward the production of broadly neutralizing antibodies. Appreciating this knowledge during immunogen construction could positively impact HIV-1 vaccine design.
Differential function and maintenance of distinct precursor T cell subsets in unimmunized mice with aging (P1302)
Authors: Renkema Kristin , Smithey Megan , Nikolich-Zugich Janko 
Published: January 2023

Abstract
While age-related T cell defects in the context of infection are being elucidated, changes in the naïve T cell pool with aging remain poorly understood. We recently showed that unimmunized old mice lose &gt;70% of Ag-specific CD8 T cell precursors, and many of the remaining precursors acquire a “virtual memory” (CD44hiCD62Lhi) phenotype. Here, we demonstrate that unimmunized TCR transgenic mice also undergo massive virtual memory conversion with age. Similar to non-transgenic mice, TCR transgenic virtual memory cells expressed increased levels of IL-15 receptor and were capable of rapid effector function upon both TCR and cytokine triggering. TCR transgenic virtual memory cells exhibited age-related delayed proliferation, suggesting an onset of proliferative senescence. This reduced proliferation could not be explained by the modest increase in expression of exhaustion molecules PD-1and LAG-3. Importantly, in Rag-sufficient OT-I mice, the highest rate of conversion to virtual memory occurred in cells that replaced the transgenic TCRα chain with endogenously recombined TCRα chains; indeed, these cells randomly expressed alternate Vα rearrangements. In contrast, OT-I Rag-/- mice, which cannot rearrange endogenous Vα, contained a small population (&lt;5%) of virtual memory cells, which did not increase with aging. These results identify a new subset of Ag-specific CD8 precursors in unimmunized mice, with distinct age-related maintenance requirements and functional capabilities.
Rapid proliferation of memory phenotype CD4+ T cells is primarily driven by self-antigens (P1330)
Authors: Becklund Bryan , Surh Charles 
Published: January 2023

Abstract
The memory phenotype (MP) CD4+ T cell pool is a heterogeneous population of cells produced upon exposure to foreign antigens and through homeostatic proliferation during transient periods of lymphopenia. Previous studies aimed at identifying the mechanisms regulating the homeostasis of the MP CD4+ T cell pool have shown that a subset of MP CD4+ T cells undergoes a rapid rate of proliferation that is dependent on T cell receptor interactions with peptides bound to MHC-II. However, it is unclear whether the rapidly proliferating MP CD4+ T cells are responding to foreign or self-derived peptide antigens. To address this question, we have analyzed the proliferation of adoptively transferred MP CD4+ T cells in a host which predominantly displays a single self-peptide bound to MHC-II and in germ-free hosts which have a dramatically reduced foreign antigen load. Our results indicate that self-peptide/MHC-II complexes are primarily responsible for driving the rapid proliferation of MP CD4+ T cells in a lymphopenic host. The vigorous response to self-antigens and acquisition of effector functions by the rapidly dividing MP CD4+ T cell subset could potentially play a role in mediating the breakdown in peripheral self-tolerance underlying lymphopenia-associated autoimmune diseases.
The forkhead transcription factor, Foxo1, fine-tunes sensitivity to homeostatic signals during calorie restriction in CD8+ cytotoxic T cells (P1292)
Authors: Gubbels Bupp Melanie , Litvin Seth , Robinson Victoria 
Published: January 2023

Abstract
In addition to longevity enhancement, calorie restriction has been reported to slow the appearance of aging-related T cell abnormalities. However, the molecular mechanism underlying this phenomenon is ill-defined. We report that short-term calorie restriction in mice conferred protection to naïve CD8+ T cells from death-by-neglect, as compared to cells isolated from mice fed ad libitum. An ortholog of the forkhead transcription factor, Foxo1, is required for the longevity benefits of calorie restriction in C. elegans. Therefore, mice with a conditional, T cell-specific deficiency of Foxo1 were also subjected to calorie restriction. Calorie restriction in the absence of Foxo1 did not result in reduced naïve CD8+ T cell death by neglect. Naïve CD8+ T cells isolated from calorie restricted mice express higher levels of the cell surface receptors, CD8 and CD127, both of which are responsible for receiving homeostatic survival signals in vivo. Thus, Foxo1 coordinates an intrinsic transcriptional response to calorie restriction that alters the sensitivity of naïve CD8+ T cells to homeostatic signals. Additional studies revealed that full calorie restriction (as opposed to restricting one component of the diet) is required for this phenomenon. To our knowledge, Foxo1 is the first transcription factor identified to contribute to altered naïve CD8+ T cell homeostasis during calorie restriction in mice.
The role of Ubiquitin Specific Protease 1 in promoting Id protein stability during T cell responses (P1300)
Authors: Omilusik Kyla , Yang Cliff , Goldrath Ananda 
Published: January 2023

Abstract
CD8+ T cells are necessary for immune responses against intracellular pathogens and tumors. The activation of T cells and subsequent differentiation into memory populations involves dramatic changes in gene expression. E protein transcription factors and their inhibitors, Id proteins, play key roles in lymphocyte development, differentiation, and maintenance. Specifically, Id2 is upregulated in effector CD8+ T cells and maintained in memory cells presumably to induce effector function. Interestingly, Id2 overexpression is also associated with lymphomas. The mechanisms controlling normal Id2 expression and how misregulation leads to transformation is largely unknown. Recently, USP1, a deubiquitinase, was shown to stabilize Id2 in osteosarcomas resulting in decreased E protein activity. Analogously, we propose a role for USP1 in posttranslational control of Id2 in T cells. Here, we show that USP1 is upregulated in CD8+ T cells upon infection and this expression change is likely mediated through the T cell receptor. Furthermore, we establish a direct interaction of Id2 and USP1 following T cell activation. By defining a regulatory role for USP1, we will have a more complete understanding of mechanisms required for controlled survival and expansion of healthy T cells and how failure of this process can lead to tumorigenesis. Ultimately, identifying USP1 as an oncogene in lymphomas will provide a novel target for therapeutic interventions.
Carbohydrates in dust mite allergen modulate Th2 immune responses (P6019)
Authors: Gour Naina , Wills-Karp Marsha 
Published: January 2023

Abstract
Asthma is a chronic inflammatory disease of the airways, driven by a Th2 immune response to allergens like house dust mite (HDM). While Th2 immune responses (IL-13 in particular) alone can induce allergic asthma, Th17 cytokines (IL-17) can exacerbate the disease. Although, the components of HDM that drive asthma remain unclear, HDM is a complex mixture including immunogenic structural moieties like carbohydrates. Such carbohydrate moieties can be recognized by pattern recognition receptors on dendritic cells (DCs) like C-type lectin receptors (CLRs). Recently, CLRs like Dectin-1 & Dectin-2 have been implicated in driving Th2 & Th17 responses against various infections. However, the role of carbohydrate recognition in modulation of HDM-induced allergic asthma remains unclear. Therefore we hypothesized that Dectin-1 & Dectin-2 induce Th2 & Th17 responses following HDM exposure. Surprisingly, Dectin-1 KO mice had exacerbated Th2 immune responses leading to enhance airway resistance. In contrast, mice in which Dectin-2 was blocked (using monoclonal antibody) had diminished HDM-induced Th2 immune responses and airway reactivity. Interestingly, neither Dectin-1 nor Dectin-2 modulated Th17 responses. Overall, our data suggests that while Dectin-1 protects against allergic asthma by negatively regulating Th2 immune responses, Dectin-2 promotes asthma by enhancing Th2 immune responses.
Cannabinoid CB2 receptors as novel target for inhibiting house dust mite induced allergic airway inflammation (P6023)
Authors: Ferrini Maria , Hong Soram , Roberts Kevan , Jaffar Zeina 
Published: January 2023

Abstract
Asthma is a chronic lung inflammatory disorder characterized by airflow obstruction, airway hyperreactivity (AHR) and bronchial inflammation in response to environmental stimuli including allergens. Allergic asthma is associated with the presence in the airways of CD4+ Th2 cells and eosinophils, together with goblet cell hyperplasia and epithelial desquamation. Recent studies have indicated that cannabis-derived compounds and cannabinoid receptor agonists have immunosuppressive and anti-inflammatory properties. In this study, we examined the effect of CB2 selective agonists on allergic airway inflammation using Derp house dust mite (HDM)-induced model of asthma. Our results revealed that the intranasal administration of nonpsychoactive CB2 agonists was highly effective at attenuating allergic airway inflammatory responses. Specifically, CB2 agonists caused a marked inhibition in the accumulation of CD4+ T cells and eosinophils into the airways and the level of Th2 cytokine production in the lungs of mice immunized and challenged with HDM. Moreover, treatment with CB2 agonists ameliorated HDM-induced AHR and mucus production. CB2 receptors were highly expressed by antigen-presenting cells in the airways during allergic inflammation. Collectively, these results demonstrate that CB2 activation leads to suppression of allergen-induced airway inflammation and AHR and may provide a novel approach for the treatment for lung inflammatory diseases such as asthma.
SPA0355, a thiourea analog, suppressed T cell activation and reduced airway inflammation in mice (P6027)
Authors: Jang Hyun-Young , Lee Sang-Myeong , Park Byung-Hyun 
Published: January 2023

Abstract
SPA0355, a thiourea analog, has reported to inhibit the nuclear factor-κB (NF-κB) pathway by targeting IκB kinase. Because NF-κB activation plays a pivotal role in the pathogenesis of allergic airway inflammation and CD4+ type 2 helper T lymphocytes (Th2 cells) cytokines production, the effect of SPA0355 on an ovalbumin-induced airway inflammation model in mice was examined. Airway hyperresponsiveness, cytokines, mucin, and eosinophilic infiltration were analyzed in bronchoalveolar lavage fluid and lung tissue. An intraperitoneal administration of SPA0355 suppressed allergen-induced NF-κB activation in the lung of sensitized mice. SPA0355 also inhibited inflammatory cell recruitment into the airways as well as the production of Th2 cytokines in bronchoalveolar fluid. In addition, SPA0355 suppressed mucin production and prevented the development of airway hyper-responsiveness. Further in vitro studies showed that SPA0355 suppressed CD4+ T cell proliferation, activation, and differentiation into Th1 and Th2 cells. These results suggest that immunomodulatory effects of SPA0355 in vivo and in vitro may provide a basis for the development of a new therapy for the allergic airway inflammation.
Intestinal epithelial cells IKKβ regulate allergic responses in the skin (P6053)
Authors: Bonnegarde-Bernard Astrid , Jee Junbae , Fial Michael , Aeffner Famke , Boyaka Prosper 
Published: January 2023

Abstract
The sites where immune responses are initiated are believed to play a key role at shaping subsequent responses at distant mucosal sites. We have previously shown that IKKβ in intestinal epithelial cells (IECs) shapes the immune responses to ingested antigens and influences airway responses to subsequent antigen exposure via regulation of IgA and Th17. People with food allergy often suffer from allergic airway and/or skin diseases like asthma or atopic dermatitis but it is unknown whether T cells sensitized in the gut promote inflammation at different mucosal surfaces through the same mechanism. Using a model of oral antigen sensitization and mice with cell-specific deletion of IKKβ, we addressed the contribution of IECs to regulatory crosstalk between the gut and skin. Control C57BL/6 mice and mice deficient in IKKβ in IEC (IKKβΔIEC) were orally sensitized by administration of ovalbumin and cholera toxin as adjuvant. All groups developed similar levels of antigen-specific IgE and IgG1 responses, but IgG2b responses were enhanced in IKKβΔIEC. Subsequent epicutaneous challenges of control mice with ovalbumin induced skin inflammation characterized by increased epidermal thickness and dermal infiltration of eosinophils. Interestingly, both the epidermal thickness and dermal infiltration of eosinophils were reduced in IKKβΔIEC. Ongoing studies will determine mechanisms underlying the protective effect of IKKβ in intestinal epithelial cells against allergic responses in the skin.
Insulin Receptor Substrate-2 negatively regulates alternative macrophage activation and allergic lung inflammation. (P6009)
Authors: Keegan Achsah , Dorsey Nicolas , Qi Xiulan , Smith Elizabeth , Dasgupta Preeta 
Published: January 2023

Abstract
Insulin Receptor Substrate (IRS)2 is an adaptor that mediates anti-apoptotic signals in response to IL-4 or IL-13 in addition to regulating insulin signaling. Studies have shown that IRS2 plays a role in IL-4-induced proliferation of CD4+ T cells and secretion of TH2 cytokines in vitro. However, the functional significance of this pathway in induction of allergic lung inflammation has not been assessed. We previously demonstrated that IL-4 induced greater phosphorylation of IRS2 and expression of genes associated with the alternative activation of macrophages (AAM) when compared to IL-13, suggesting that IRS2 may be required for AAM differentiation. To examine the role of IRS2 in AAM gene induction and pulmonary inflammation, we utilized IRS-2-/- mice. Surprisingly, IRS2-/- mice developed enhanced pulmonary inflammation with significantly increased recruitment of eosinophils and macrophages in comparison to IRS2+/+ mice. Additionally, greater numbers of FIZZ1, YM1 and Arginase1 transcripts were detected in response to IL-4 or IL-13 in macrophages lacking IRS2 in vitro. This also correlated to increased YM1 protein expression in macrophages in vivo in the allergic airways in IRS2-/- mice. Interestingly, IRS2+/- mice demonstrated a gene dosage effect; they developed intermediate levels of inflammation, cellular infiltration and AAM gene/protein expression. Thus, this study identifies a previously unrecognized role for the IRS2 pathway in suppressing asthma responses.
PTX3 modulates airway hyperresponsiveness and immune response to OVA in a murine model of asthma (P6011)
Authors: Balhara Jyoti , Shan Lianyu , Soussi Gounni Abdelilah 
Published: January 2023

Abstract
Pentraxin-3 (PTX3) is a member of the long pentraxins family. It activates the innate and adaptive immune systems, playing an important role in providing immunity against various pulmonary infections. Considering its role in fostering lung immunity, we examined the role of PTX3 in asthma. We have recently demonstrated an enhanced expression of PTX3 in bronchial biopsies of allergic asthmatics that correlated with the disease severity. In this report, we assessed the effect of PTX3 deficiency in a murine model of OVA-induced asthma. Sensitized PTX3 Knockout (KO) mice exhibited an enhanced airway and tissue resistance in response to methacholine (MCh) in contrast to their WT counterparts. We observed an increase in the infiltration of inflammatory cells in BALF obtained from PTX3 KO mice upon OVA sensitization/challenge as compared to their WT littermates. However peribronchial and perivascular inflammation and goblet cells hyperplasia showed no significant difference in both mouse strains. Further we found an enhanced induction of IL-4, IFN-gamma, IL-17 and IL-10 production in the lungs of PTX3 KO mice as compared to WT mice upon OVA challenge. In lymph node, IL-17A recall response was found to be greater in PTX3 KO mice than WT mice but no difference was observed in term of IL-4, IFN-gamma and IL-10 production. Taken together, we conclude that lack of PTX3 predisposes mice to airway hyperresponsiveness and an enhanced inflammation.
CCL3 and CCL4 secretion by T regulatory cells attracts CD4+ and CD8+ T cells (P1077)
Authors: Wang Adele , Patterson Scott , Marwaha Ashish , Tan Rusung , Levings Megan 
Published: January 2023

Abstract
FOXP3+ T regulatory cells (Tregs) function to restrain immune responses. Accumulating evidence has shown that Tregs mediate their suppression by migrating to tissues based on their distinct expression of chemokine receptors. Yet how Tregs ensure they are close to their targets is unknown. Using ELISA and intracellular staining we discovered that both human and mouse Tregs produce CCL3 and CCL4, ligands for CCR5. Since chemokines recruit immune cells and the broad suppressive activities of Tregs require intimate cell proximity, we hypothesized that the secretion of the pro-inflammatory chemokines may bring immune cells closer to Tregs to be suppressed. To determine whether Tregs can recruit CD4+ and CD8+ cells via a CCR5-dependent mechanism, we performed migration assays and showed CCL3- and CCL4- containing-supernatants from Tregs attracted both subsets of T cells as well Tregs. Additionally, CCR5-/- T cells had a significantly reduced capacity to migrate towards Tregs in vitro and in vivo, supporting that chemokine signalling through CCR5 is critical. Furthermore, decreased proportion of FOXP3+CCL3+ Tregs was observed in patients with type 1 diabetes compared to healthy controls, implying that the altered chemokine secretion could contribute to the inadequate Treg function. These results suggest that active recruitment of their targets of suppression may be a novel mechanism of action by Tregs and that this pathway could be a potential therapeutic target in autoimmunity.
Elucidation of the mechanism of cell type specific IRF-4-mediated transcription in CD4+ T cells (P1081)
Authors: Spolski Rosanne , Li Peng , Liao Wei , Wang Lu , Leonard Warren 
Published: January 2023

Abstract
IL-21 plays a key role in Th17 differentiation. Interferon (IFN) regulatory factor 4 (IRF4) is a critical regulator of differentiation in B and T cells, and Th17 differentiation is defective in Irf4 KO CD4+ T cells. In B cells, IRF4 is known to cooperatively bind DNA in partnership with the Ets family protein PU.1. However, PU.1 is not expressed in most T cells even though IRF4 is active within these cells, and the functional transcription factor complex that regulates Th17-specific genes was not known. Genome-wide Chip-Seq analysis was used to demonstrate that in T cells, IRF4 binds to a novel composite DNA motif that includes AP1 motifs and which we named AP1-IRF4 composite elements (AICEs). Moreover, IL-21-regulated genes in Th17 cells have co-localized binding of IRF4, BATF, and JUN family proteins, and the genes encoding these transcription factors are themselves regulated by IL-21 in CD4+ T cells. RNA-seq analysis revealed subsets of genes whose regulation by IL-21, either positive or negative, depends on IRF4, and reporter studies demonstrated that IL-21-induced transcription of these genes was dependent on both IRF4 and AP1 transcription factor binding. Our results demonstrate that by utilizing distinct binding partners and DNA sequences, IRF4 mediates cell-type and stimulus-specific functions in multiple lymphocyte lineages.