bluuebunny/crossref_metadata_2025_split huggingface dataset:
IL-23 is required for long-term control of Mycobacterium tuberculosis and B cell follicle formation in the infected lung. (150.1)
Authors: Khader Shabaana , Guglani Lokesh , Rangel-Moreno Javier , Fountain Jeffrey , Martino Cynthia , Pearl John , Kolls Jay , Randall Troy , Cooper Andrea 
Published: January 2023

Abstract
IL-23 is required for effective IL-17 responses to aerosol infection with Mycobacterium tuberculosis (Mtb), however it does not appear to impact early control of bacterial growth in the lung. By extending the time course of infection using mice deficient for the p19 component of the IL-23 cytokine, we report that there is increased bacterial growth in the lungs of these mice compared to wild type infected mice. This increased bacterial growth is associated with decreased maintenance of B cell follicles within lungs of infected mice. While mRNA expression for molecules associated with limiting bacterial growth such as Interferon gamma (IFNγ) were equivalent between wild type and IL-23p19 deficient mice, reduced expression of both IL-17 and IL-22 mRNA was observed in IL-23p19 deficient Mtb-infected lungs. Importantly, we show that in mice deficient for IL-23p19, B cell follicle size was reduced during chronic Mtb infection and this was temporally associated with the increased bacterial burden. In mice deficient in the IL-17 receptor (IL-17R), B cell follicle generation was affected early in infection whereas the absence of IL-22 influenced the size of B cell follicles in the mid-term. Interestingly, the absence of IL-22 or IL-17R alone did not impact bacterial control. Thus, we show novel data that while IL-23 is required for long term control of Mtb growth in the lung, there is a compensatory effect of IL-22 and IL-17 during tuberculosis.
Memory CD8 T cell responses to IL-15 transpresentation are impaired in the absence of ICAM-1 (150.6)
Authors: Stonier Spencer , Acero Luis , Schluns Kimberly 
Published: January 2023

Abstract
Homeostatic proliferation is important for the long-term maintenance of memory CD8 T cells and is mediated by trans-presentation of IL-15. Since IL-15 transpresentation requires a cell-cell interaction, we asked whether ICAM-1 is important for IL-15 responses in memory CD8 T cells. After transfer into either Wt or ICAM-1-/- mice, Wt memory CD8 T cells displayed less homeostatic proliferation and decreased survival in the absence of ICAM-1. To determine whether the absence of ICAM-1 was directly affecting IL-15 transpresentation, IL-15 responses of isolated CD8 T cells were analyzed after culturing with DCs. IL-15-driven proliferation and STAT5 phosphorylation in memory CD8 T cells were completely abolished in cultures with ICAM-1-/- DCs or with blocking Ab against ICAM-1. Overall, this is the first report that establishes a link between ICAM-1 and IL-15 transpresentation and serves to demonstrate the importance of specific adhesion molecules in facilitating IL-15-mediated responses in memory CD8 T cells.
Role of inflammasome signaling in development and function of mast cells (151.11)
Authors: Mortaz Esmaeil , Folkerts Gert , Kraneveld Aletta , Kool Mirjam , Lambrecht Bart , Garssen Johan , Redegeld Frank 
Published: January 2023

Abstract
The inflammasome is a cytosolic molecular complex containing a ASC,caspase1 and NALP that mediate the maturation of the proinflammatory cytokines IL-1β by caspases-1. NALP3 is an intracellular receptor involved in the recognition of pathogen associated molecular patterns (PAMPs).The inflammasome signal transduction promotes the maturation of inflammatory cytokines 1L-1β.The levels of 1L-1β has been shown increased in lung disease like asthma and emphysema.Mast cells(MC)play as effector cells for IgE mediated allergic diseases.Besides, recent evidence indicates that MCs also function as important cells in immune surveillance. Not much is known about role of inflammasomes in biology and development of mast cells.In this study we investigated the role of NALP3/ASC in mast cells.Development and function of mast cells, derived from a culture of bone marrow cells of wild-type, ASC-/-, NALP3-/-mice was studied. Bone marrow cells were cultured in presence for 3 weeks. After 3 weeks the responsiveness of mast cells to IgE/Ag and LPS was studied.Results:We found that in ASC-/-,NALP3-/- mast cells,the cellular maturation and differentiation was decreased as evidenced by a lower expression of c-kit and FcϵRI. Degranulation and the production of TNF-α,IL-6 and IL-1β after stimulation by IgE/Ag or LPS was significantly lower in NALP3-/-,ASC-/- cells compared to control cells.Our study demonstrates that NALP3/Asc plays role in maturation,differentiation and function of mast cells in vitro.
Genetic analysis of basophil function in vivo (151.22)
Authors: Sullivan Brandon , Liang Hong-Erh , Bando Jennifer , Wu Davina , Cheng Laurence , McKerrow James , Allen Chris , Locksley Richard 
Published: January 2023

Abstract
Contributions by basophils to allergic and helminth immunity remain controversial. Using sensitive IL-4 reporter alleles, we demonstrate that basophil IL-4 production occurs by a CD4 T cell-dependent process restricted to affected peripheral tissues. We genetically marked and specifically deleted basophils and demonstrate that basophils do not mediate Th2 priming in vivo. Two-photon imaging confirmed that basophils do not interact with antigen-specific T cells in lymph nodes, but can engage in prolonged serial interactions with T cells in lung tissues. Although targeted deletion of IL-4/IL-13 in either CD4 T cells or basophils minimally impacted worm clearance, deletion from both lineages demonstrated a nonredundant role for basophil cytokines in primary helminth immunity.
Anti-FcϵRIα mAb-based therapy can suppress IgE-mediated disease (151.4)
Authors: Khodoun Marat , Krishnamurthy Durga , Strait Richard , Kucuk Yesim , Finkelman Fred 
Published: January 2023

Abstract
IgE contributes to allergy pathogenesis by mediating Ag crosslinking of the high affinity IgE receptor, FcϵRI, on mast cells and basophils, which results in massive secretion of cytokines, vasoactive mediators, and proteolytic enzymes. We evaluated the ability of MAR-1, a hamster anti-mouse FcϵRIα mAb, to suppress murine IgE-mediated disease. MAR-1 and IgE compete for binding to FcϵRI, but MAR-1, unlike IgE, removes mast cell FcϵRI and kills basophils. Although MAR-1 does not remove FcϵRI/IgE complexes from mast cells, receptor turnover allows in vivo treatment with MAR-1 for 22 days to remove nearly all mast cell FcϵRI. MAR-1 itself activates basophils and mast cells and induces anaphylaxis, but anaphylaxis can be prevented by either antihistamine plus corticosteroid pretreatment or serial injection of increasing doses of MAR-1 (rapid desensitization). MAR-1 treatment immediately prevents subsequent mast cell priming with Ag-specific IgE mAb, while treatment for 22 days prevents Ag-induced mast cell activation in mice injected with Ag-specific IgE mAb prior to treatment initiation. A single dose of MAR-1 fully suppresses established moderate food allergy. Although MAR-1 suppression of established severe food allergy is limited by development of anti-hamster IgG Ab; this is prevented and disease fully suppressed by additional treatment with a single dose of anti-CD4 mAb. These observations suggest practical approaches to treat established IgE-mediated allergic disorders.
Expression of mouse and human TIGIT on follicular T helper cells and other lymphocytes (152.10)
Authors: Funatake Castle , Kang William , Araji Soha , Li Shourong , Atteberry Brandi , Huang Qiulong , Just Peggy 
Published: January 2023

Abstract
T cell immunoreceptor with Ig and ITIM domains (TIGIT) is a newly identified member of the polio virus receptor family. In humans, its expression has been reported on NK cells, regulatory T cells (Treg), memory CD4 T cells, follicular T helper cells (Tfh), and CD8 T cells, but not on B cells or naïve CD4 T cells. In mice, mRNA for TIGIT has been observed in Tfh but not naïve T cells. We examined the expression of TIGIT on lymphocytes in mice and humans using two novel antibodies, clone GIGD7 and MBSA43, respectively. We found that the expression patterns on unstimulated lymphocytes were dissimilar between mice and humans, whereas expression following activation was more consistent. For the first time, we show that TIGIT is expressed on the surface of mouse Tfh, consistent with studies examining mRNA and similar to previous observations in humans. Finally, the response of memory T cells in vitro was slightly increased when normal human peripheral blood cells were stimulated in the presence of MBSA43 to block TIGIT, consistent with its role as an inhibitory receptor. These two antibodies will facilitate the characterization of TIGIT on Tfh and Treg, as well as human memory T cells and NK cells and will help to elucidate the role of this inhibitory receptor during immune responses.
C6-ceramide facilitates IL-12-mediated T helper-1 cell differentiation through a COX-2/PGE2-dependent pathway (152.17)
Authors: Kue Chin Siang , Jung Mi Young , Kim Tae Sung 
Published: January 2023

Abstract
Ceramides, lipid molecules that are found predominantly in the plasma membrane of a cell, can serve as a second messenger and have been known to perform a number of cellular functions. Our study was designed to investigate the effect of ceramides on T helper cell responses and their underlying mechanisms. We found that a cell-permeable C6-ceramide (C6) together with IL-12 synergistically increased the populations of IFN-γ+ T cells and up-regulated IFN-γ production from CD4+ T cells, whereas C2-ceramide and long chain ceramides (C16 and C24) did not affect. C6 treatment increased the expression of T-bet, a master transcription factor of Th1 responses, in a dose-dependent manner. Moreover, C6 induced expression of cyclooxygenase-2 (COX-2) accompanied by prostaglandin E2 (PGE2) production in CD4+ T cells. The IFN-γ+ T cells populations and IFN-γ production induced by C6 were significantly suppressed by both a COX-2 specific inhibitor (NS398) and an anti-PGE2 neutralizing antibody in a dose-dependent manner. T-bet expression was also decreased by NS398 treatment. Taken together, C6 promotes the production of PGE2 in CD4+ T cells through a COX-2 dependent mechanism, thereby facilitating Th1 cell differentiation. These results suggest that C6 can be utilized in the therapeutics of diseases such as cancer and allergic by enhancing the Th1 activity.
Egr3 promotes the development of inflammatory γδ T cells (152.2)
Authors: Parkinson Rose , Powell Jonathan 
Published: January 2023

Abstract
Though Egr3 is known to inhibit a Th1 response, its role in Th17 development is unclear. We show that CD4+ T cells from mice overexpressing Egr3 (Egr3 TG) produce more IL-17 than wildtype controls. This increase is not cell intrinsic, as naïve CD4+ T cells from Egr3 TG mice do not produce IL-17 upon activation and IL-6 and IL-23 mRNA are elevated in lymphoid organs. Egr3 TG mice also have increased numbers of CD4- CD8- T cells, most of which express the γδ TCR. These γδ T cells strongly express IL-17 and IL-6, suggesting that they are capable of directing CD4 T cells toward a Th17 phenotype. We find a similar increase in the number of γδ T cells in the mucosal epithelia of Egr3 TG mice. Consistent with our previous results, Egr3 TG mice exhibit more lung inflammation, IL-17 production, weight loss, and mortality in a bleomycin-induced pulmonary fibrosis model. We also tested the susceptibility of these mice in a DSS-induced colitis model, where the role of IL-17 is less clear and γδ T cells may serve a protective role. In this model, Egr3 TG mice have decreased TNFα production, decreased rectal bleeding and increased overall survival. Our data suggest that Egr3 induces of one or more subsets of γδ T cells, which are inflammatory in select mucosal settings. Future studies will clarify the precise mechanism of enhancement or protection in models of mucosal inflammatory disease.
Curcumin attenuates decline of CD69 expression on CD4+ T cells and induces generation of CD25hiFoxp3+ T cells through TGF-β1 production (152.22)
Authors: Kim Gi Rak , Jang Mi Seon , Son Young Min , Han Seung Hyun , Yun Cheol-Heui 
Published: January 2023

Abstract
Curcumin is a promising candidate as a natural medicinal agent to treat chronic inflammatory diseases. However, little is known about curcumin-mediated CD4+ T cell regulation, which contributes to the therapeutic effects of curcumin. Here, we report that curcumin inhibits T-cell receptor (TCR)-triggered immune responses of CD4+ T cells through suppression of proliferation, cytokine production and differentiation of CD4+ T cells. Intriguingly, spontaneous decline of CD69 expression was attenuated by curcumin treatment, which continued until 6 days of culture. We showed that curcumin-mediated CD69 up-regulation was dependent on extracellular signal-regulated kinase 1/2 (ERK1/2) signaling. Concomitantly, the expressions of C-C motif chemokine receptor 7 (CCR7), L-selectin and transforming growth factor-β1 (TGF-β1) were also increased. TGF-β1 production was moderate, but was high enough to lead to the late generation of CD25hiFoxp3+CD4+ T cells and to maintain prolonged suppression of CD4+ T cell activation. These findings suggest that the immunoregulatory role of curcumin is effective for CD4+ T cells.
Suppressor of cytokine signaling-1 contributes to peripheral regulatory T cell stability in an inflammatory environment. (152.24)
Authors: Collins Erin , Jager Lindsey , Dabelic Rea , Lau Ken , Haider Mohammed , Johnson Howard , Larkin III Joseph 
Published: January 2023

Abstract
Suppressor of cytokine signaling-1 deficient mice (SOCS1-/-) die of a T cell mediated inflammatory, autoimmune disease by 3 weeks of age. The inflammation mediated by excessive interferon γ signaling and leukocyte infiltration results in the destruction of many vital organs. Significantly, numerous mouse models of inflammatory autoimmune disease have been associated with a deficiency in Foxp3+ regulatory T cells. Indeed, SOCS1-/- mice possessed a reduction in peripheral Tregs, despite enhanced thymic development. The adoptive transfer SOCS1+/+ Tregs or CD4+ T lymphocytes mediated an increased, yet limited, survival in the SOCS1-/- mice. However, the adoptive transfer of CD4+ T lymphocytes in conjunction with SOCS1-KIR, a mimetic peptide sufficient to partially restore SOCS1 function, resulted in 30% of the mice living beyond 5 weeks. Moreover, the combined treatment mediated a decrease in leukocyte infiltration into vital organs, and a decrease in effector CD4+ cells. Additionally, the decrease in inflammation was associated with an increase in the peripheral Foxp3+ regulatory T cell population. Collectively, these results suggest that the SOCS1-KIR/CD4+ T cell combined treatment synergistically promoted long-term survival of the SOCS1-/- mice by restoring peripheral Tregs. Furthermore, these data propose that SOCS1 contributes to peripheral Treg stability under inflammatory conditions.
Identification of the E3 deubiquitinase USP21 as a positive regulator of GATA3 (152.25)
Authors: Zhang Jing , Chen Chen , Gao Yayi , Lin Fang , Tsun Andy , Li Bin 
Published: January 2023

Abstract
TCR signaling induces GATA3 expression in FOXP3+ Treg, but the underlying mechanism for GATA3 accumulation and its role in Treg function remains unclear. Here we identify the E3 deubiquitinase USP21 as a positive regulator of GATA3 in FOXP3+ T cells. By screening for regulators which may affect the function of key transcription factors essential for T cell lineage differentiation and function, we found that USP21 dramatically increases the cellular level of GATA3. Reciprocal co-immunoprecipitation studies indicated that USP21 can interact with GATA3 in vivo. Overexpression of wild type USP21, but not the enzymatically inactive mutant C221A, specifically promotes the up-regulation of GATA3 protein expression, suggesting that the deubiquitinase activity of USP21 is essential for the upregulation of GATA3. Moreover, we found that T cell activation via TCR and CD28 costimulation may upregulate the level of USP21 and GATA3 in FOXP3 expressing T cells. shRNA mediated knockdown of USP21 can prevent GATA3 accumulation after T cell activation, suggesting that the mechanism by which USP21 stablizes GATA3 may occur through preventing GATA3 degradation. Functionally, overexpression of wild-type USP21 promotes GATA3 mediated upregulation of IL-4. Our studies have identified a unique pathway to upregulate GATA3 activity at posttranslational level by reversing ubiqutination-mediated protein degradation.
Glycogen synthase kinase-3 is an early determinant in the differentiation of pathogenic Th17 cells. (152.3)
Authors: Beurel Eleonore , Yeh Wen-I , Michalek Suzanne , Harrington Laurie , Jope Richard 
Published: January 2023

Abstract
CD4+ T cells are critical for host defense but also drive immune-mediated diseases. The classical view of Th1 and Th2 subtypes of CD4+ T cells was recently revised by the identification of the Th17 lineage that produces IL-17 and are critical in autoimmune disease pathogenesis. Mechanisms controlling the differentiation of Th17 cells have been described, but few feasible targets for therapeutically reducing Th17 cells are known. The generation of Th17 cells requires IL-6 and activation of STAT3. During polarization of CD4+ T cells to Th17 cells, we found that inhibition of glycogen synthase kinase-3 (GSK3) blocked IL-6 production, STAT3 activation, and polarization to Th17 cells. Polarization of CD4+ T cells to Th17 cells increased by 10-fold GSK3β protein levels in Th17 cells, while GSK3β was unaltered in Treg cells. Diminishing GSK3 activity pharmacologically or molecularly blocked Th17 cell production, and increasing GSK3 activity promoted polarization to Th17 cells. In vivo inhibition of GSK3 in mice depleted constitutive Th17 cells in intestinal mucosa, blocked Th17 cell generation in the lung following Francisella tularensis infection, and inhibited the increase in spinal cord Th17 cells and disease symptoms in the experimental autoimmune encephalomyelitis (EAE) mouse MS model. These findings identify GSK3 as a critical mediator of Th17 cell production, and indicate that GSK3 inhibitors provide a potential therapeutic intervention to control Th17-mediated diseases.
Identification and characterization of a novel and functionally distinct human memory CD4+CD25INTFOXP3- population (152.30)
Authors: Triplett Todd , Curti Brendan , Weinberg Andrew 
Published: January 2023

Abstract
Surface expression of the IL-2 receptor α-chain (CD25) has been used as a marker to discriminate between CD4+CD25HiFOXP3+ Tregs and resting CD4+CD25-FOXP3- non-Tregs. However, using a new monoclonal antibody we have revealed a novel human CD4+CD25INTFOXP3- T-cell population that expresses intermediate levels of CD25 and constitutes ~ 40% of resting human CD4+ T cells, the majority of which are memory cells. Further analysis revealed that the CD25NEG and CD25INT memory populations are stable populations composed of distinct memory subsets. The CD25NEG population contains the vast majority of late differentiated EOMES+CD28-GranzymeB+ memory cells that are expanded in Lupus patients and respond to antigens associated with chronic immune responses (CMV). In contrast, the CD25INT population contains memory cells that primarily respond to antigens associated with recall antigen responses (FLU) and produce a wider array of cytokines (IL-17, IL-10, IL-5, IL-9). We also found that compared to the CD25NEG and Treg memory populations, the CD25INT population is differentially affected by rhIL-2 in vitro and in vivo when cancer patients are treated with IL-2-specific immunotherapy. Collectively, these results show that in humans a larger proportion of CD4+ T cells express the high affinity IL-2 receptor than originally thought and that expression of CD25 may be used as a surface marker to discriminate functionally distinct memory populations that are uniquely affected by IL-2.
Denditic cells and regulatory T cells: development, crosstalk and consequences (152.31)
Authors: Darrasse-Jeze Guillaume 
Published: January 2023

Abstract
Dendritic cells (DCs) play a major role of immune sentinels of our body. These cells capture, process and presents both foreign and self antigens to lymphocytes that activate immune responses or maintain immune tolerance. Despite a growing interest, their behavior remains mysterious. We have characterized in vivo at the cellular and molecular level, their development, their homeostasis and their intercellular communication with natural regulatory T cells (Tregs). We had previously found that Tregs were essential for maintaining normal numbers of dendritic cells (DCs): when Tregs are depleted, there is a compensatory Flt3-dependent increase in DCs. We now show that Treg homeostasis is maintained in vivo by the existence of a feedback regulatory loop between DCs and Tregs. We find that loss of DCs leads to a loss of Tregs, and that the remaining Tregs exhibit decreased Foxp3 expression. The DC-dependent loss in Tregs leads to an increase in the number of T cells producing inflammatory cytokines, such as interferon gamma and interleukin 17. Conversely, increasing the number of DCs leads to increased Treg division and accumulation by a mechanism that requires major histocompatibility complex II expression on DCs. The increase in Tregs induced by DC expansion is sufficient to prevent type 1 autoimmune diabetes and IBD, which suggests that interference with this feedback loop will create new opportunities for immune-based therapies.
Modeling the mechanisms of action underlying the plasticity of the CD4+ T cell differentiation process (152.34)
Authors: Carbo-Barrios Adria , Hontecillas Raquel , Climent Montse , Hoops Stefan , Lu Pinyi , Wendelsdorf Katherine , Eubank Stephen , Marathe Madhav , Bassaganya-Riera Josep 
Published: January 2023

Abstract
Mathematical and computational modeling facilitates concurrent multiparametric analyses of dynamic biological processes. Herein we describe a network model illustrating intracellular pathways controlling a naïve T cell differentiation into Th1, Th2, Th17 or iTreg phenotypes. The model is comprised of 37 differential equations representing 40 reactions and 81 species. The COmplex PAthway SImulator software has been used for model calibration and it shows that our model adequately computes the differentiation of CD4 T cells into the four phenotypes. Moreover, our network includes the nuclear transcription factor peroxisome proliferator activated receptor γ (PPARγ) that modulates the Th17/iTreg plasticity and is highly expressed during IL-4-induced Th2 differentiation. Local model sensitivities demonstrate that PPARγ activation increases the production of FOXP3 when the system is driven into Th17 differentiation. The prediction of this model was validated in vitro using primary mouse CD4+ T cells differentiated into Th17 and treated with 0, 0.25, 0.5, 1, 2, 4, 10 and 40 μM rosiglitazone, a PPARγ agonist. Our differentiation studies confirmed the prediction of our model that increasing concentrations of rosiglitazone in Th1-induced CD4 T cells decrease INFγ and Tbet levels, and increase GATA3 expression in Th2-induced T cells. These data support the prediction of our model regarding the modulation of intracellular networks controlling fate and function of CD4+ T cells by PPARγ.