bluuebunny/crossref_metadata_2025_split huggingface dataset:
TIM1 engagement on invariant NKT cells inhibits IFN-γ production in the presence of TCR stimulation in vitro and in vivo (33.21)
Authors: Kim Hye Sung , Chung Doo Hyun 
Published: January 2023

Abstract
T cell immunoglobulin domain and mucin domain (TIM)1, expressed on Th2 cells, regulates immune responses by modulating cytokine production. However, the functional roles of TIM1 have not been examined in NKT cells. Therefore, we investigated the immunologic effects of TIM1 on NKT cells using anti-TIM1 mAbs. Mouse NK1.1+TCR-β+ and α-GalCer/CD1d dimmer+ NKT cells constitutively expressed TIM1 on cell surface. TIM1 engagement on NKT cells using a series of anti-TIM1 mAbs suppressed IFN-γ production in the presence of TCR stimulation in vitro, whereas its effects on Th2 cytokines production of NKT cells were various depending on anti-TIM1 mAb clone. The injection of various anti-TIM1 mAbs into B6 mice also reduced IFN- γ levels in the sera with the coinjection of α-galactosylceramide (α-GalCer), and one of anti-TIM1 mAbs enhanced Th2 cytokines. Moreover, TIM1 engagement increased p27 and GATA-3 expression but reduced T-bet expression in NKT cells in the presence of TCR engagement. The adoptive transfer of NKT cells preincubated with a series of anti-TIM1 mAbs aggravated bleomycin-induced pulmonary fibrosis in NKT cell-deficient mice by suppressing IFN-γ production. Taken together, TIM1 costimulation inhibits IFN- γ production by NKT cells, which may regulate immune responses in vivo, and be a useful therapeutic candidate for various immune diseases.
Agonistic monoclonal antibody against DR5 induces ROS aggregation, sustained JNK activation and Endo G release in Jurkat leukemia T lymphocytes (33.22)
Authors: Zheng Dexian , Chen Caifeng , Chen Feng , Liu Yanxin 
Published: January 2023

Abstract
We previously reported that AD5-10, a novel agonistic mAb to DR5, possessed a strong cytotoxic activity in various tumor cells. In this study, we further demonstrated the ROS generation, sustained activation of JNK, loss of mitochondrial membrane potential, and release of Endo G in Jurkat leukemia T lymphocytes upon AD5-10 stimulation. The dominant negative JNK, but not p38, enhanced NF-κB activation, suppressed caspase-8 recruitment in DISC, reduced the dysfunction of mitochondria, therefore, inhibited the cell death in these cells. The data may throw light on the therapeutic strategy for T lymphocyte leukemia and solid tumors.
We further investigated the sensitivity of lung cancer cells to AD5-10. A549 and SCLC showed a moderate sensitivity and H460 resistant to the mAb, which was not related to DR5 expression, but c-FLIPL expression and cleavage. Inhibition of c-FLIPL by siRNA significantly enhanced AD5-10-induced cell death. The sensitizing effect was associated with decreased expression of Bid and Bcl-XL, change of mitochondrial membrane potential, release of cytochrome c, and caspase activation. Immunohistochemistry assay revealed that c-FLIPL was expressed in 87.9% of the lung carcinoma tissues from the patients, but little in the normal controls, suggesting that inhibition of c-FLIPL might be a potential strategy for lung cancer therapy.
Dynamic αβ T cell receptor quaternary structure is linked to its mechanosensor function (33.27)
Authors: Kim Sun Taek , Takeuchi Koh , Sun Zhen-Yu J. , Touma Maki , Wagner Gerhard , Reinherz Ellis L. 
Published: January 2023

Abstract
The T cell receptor (TCR) mediates antigen recognition and T cell activation via its dimeric αβ, CD3εγ, CD3εδ and CD3ξξ subunits. A structural mechanism integrating both functions remains elusive. Here, anti-CD3 mAbs, NMR cross-saturation plus chemical shift mapping and mutational analyses were used to show that site-specific binding topology and TCR quaternary change are essential for activation. Two agonist mAbs footprint to the membrane distal CD3ε lobe, whereas a non-agonist mAb binds to the cleft between CD3ε and CD3γ. T cell triggering is not linked to mAb affinity or CD3ε binding stoichiometry per TCR but requires an intact TCRβ-CD3εγ module. CD3γ ectodomain mutants or an Fab directed toward the lever-like Cβ FG loop near the agonist mAb site inhibit antigen-dependent activation by preventing quaternary change upon ligand binding. Flexible elongated TCRα (25-26 aa) and TCRβ (19 aa) membrane stalks versus rigid compact CD3ε, CD3γ, and CD3δ (5-10 aa) G-strands and CxxC membrane proximal motifs permit dynamic TCRαβ movement over asymmetric CD3 heterodimers upon p-MHC binding. Extracellular mechanical torque on the TCR resulting from specific p-MHC binding during T cell scanning of APCs can initiate quaternary structure changes within the TCR, triggering downstream signaling. These findings suggest that the TCR is a specialized mechanosensor, converting mechanical energy from immune surveillance into a biochemical signal at no energetic cost.
The co-regulatory molecule TIGIT contributes to suppressor function of regulatory T cells. (33.29)
Authors: Grogan Jane L , Yu Xin 
Published: January 2023

Abstract
TIGIT is a co-regulatory molecule expressed on regulatory, memory and activated naïve T cells. Poliovirus receptor (PVR, CD155) was identified as the high-affinity receptor for TIGIT. TIGIT can induce immunoregulatory dendritic cells via ligation of PVR that can inhibit T cell responses in vitro and in vivo, in part due to IL-10 induction. We further examined the role of TIGIT on human T regulatory cells (Treg). Isolated human TIGIT+ T cells inhibited CD4+CD25-TIGIT- naïve T cell proliferation in vitro in the presence of APC. An anti-TIGIT antagonist antibody inhibited Treg suppression in vitro. Transwell experiments show that TIGIT-mediated suppression of effector cells requires DC-Treg cell-cell interaction. Furthermore, the TIGIT-mediated Treg suppression could be replaced by TIGIT.Fc alone. These data suggest that TIGIT plays a role in T regulatory cell function via interacting with PVR on APC.
CD46-induced regulatory T cells suppress Mycobacterium tuberculosis-specific effector T cell responses (33.5)
Authors: Truscott Steven M , Abate Getahun , Price Jeffrey D , Kemper Claudia , Atkinson John P , Hoft Daniel F 
Published: January 2023

Abstract
Human regulatory T cells can be generated through a number of known pathways in vivo and in vitro. Simultaneous engagement of the TCR and complement regulator CD46 on human CD4+ T cells induces adaptive Treg development. These CD46-induced Treg, also known as 'complement-induced Treg' or 'cTreg,' have been shown to suppress bystander CD4+ T cells activated in vitro with crosslinking antibodies to CD3 and CD28. Here we offer the first description of cTreg suppression of human effector T cells in an APC-dependent system of pathogen infection. We found that soluble molecules secreted by cTreg suppress Mycobacterium tuberculosis-specific CD4+, CD8+, and γδ T cell responses. These immunosuppressive effects were mediated in part by IL-10 and in part by other as yet unidentified soluble factors acting synergistically with IL-10. In addition, our results indicate that different mechanisms may be involved in the suppression of αβ and γδ T cells. We further show that APC functions were not affected by cTreg, indicating direct suppression of pathogen-specific T cells. Modulating the immunosuppressive functions of this Treg subset could lead to improved tuberculosis therapeutics or vaccines.
Autoregulatory B-1 cells (34.13)
Authors: Sindhava Vishal J , Bondada Subbarao 
Published: January 2023

Abstract
Immunological tolerance in the periphery is mediated by clonal inactivation mechanisms as well as by regulatory cells. Recent studies showed that high IL-10 producing B-cell subsets with varying phenotype can regulate different immune responses in numerous mouse models. We found that, in comparison to B-2 cells, peritoneal B-1a cells are hyporesponsive to TLR stimulation in proliferation and antibody secretion, but produce very high amounts of IL-10. We hypothesized that the high IL-10 levels work in an autocrine manner and autoregulate B-1 cells that are prone to produce autoantibodies. Accordingly, neutralization of IL-10 enhanced peritoneal B-1, but not splenic B-2 cell proliferation and differentiation to all TLRs tested. Moreover, IL-10-/- peritoneal B-1 B-cells responded better than wild type B-1 cells to TLR stimulation. Co-stimulation with CD40 and BAFF, but not IL-5, overcame the inhibitory effect of IL-10. The increased IL-10 production was unique to peritoneal B-1 B-cells, since splenic B-1 B cells behaved like splenic B-2 cells, in terms of IL-10 production and proliferation. This autoregulation appears to have physiological significance since IL-10 knock out peritoneal B-1 cells controlled Borrelia hermsii infection better than wild type B-1 cells. Thus the IL-10 mediated autoregulation of B-1 cells may have a role in the control of autoimmunity and infection. (Supported by NIH grants to SB).
Cytokine-secreting follicular T cells shape the antibody repertoire (34.19)
Authors: Reinhardt Richard Lee , Liang Hong-Erh , Locksley Richard M. 
Published: January 2023

Abstract
High-affinity antibodies are critical for host protection against pathogens and toxins, and underlie successful vaccines. Generation of such antibodies requires T cell-dependent help, which mediates germinal center (GC) reactions where mutation and selection of B cells expressing receptors with high-affinity for antigen occurs. Follicular CD4 T (TFH) cells, which comprise only 5-10% of GC cells, have been imaged in stable conjugates with GC B cells, but no functional analysis of B/TFH cell interactions in GC has been performed. Using an IL-4 reporter system, we show that TFH cells comprise essentially all of the cytokine-secreting T cells in lymph nodes and are functionally distinct from T cells secreting the same cytokine in peripheral tissues. TFH cells with different cytokine profiles could be visualized in the same GC and could be isolated as conjugates with B cells undergoing cytokine-specific immunoglobulin isotype class switching, expressing high levels of AID, and evidence of somatic hypermutation. These findings support a model wherein GC B cells compete for cytokines produced by rare antigen-specific GC TFH cells that mediate highly localized effects and regulate the size, affinity and isotype of the B cell antibody response.
Negative regulation of IgA production by the Fc&[alpha]/&[mu]R, an Fc receptor for IgA and IgM (39.13)
Authors: Kurita Naoki , Honda Shin-ichiro , Cho Yukiko , Usui Kenta , Shibuya Akira 
Published: January 2023

Abstract
Fc&[alpha]/&[mu] receptor (Fc&[alpha]/&[mu]R) is a novel Fc receptor for both IgA and IgM. Fc&[alpha]/&[mu]R transcript is expressed in the gut as well as spleen and lymph node. The immunohistological analysis showed that Fc&[alpha]/&[mu]R is highly expressed on follicular dendritic cells (FDCs) in germinal centers and at lesser extent on B cells of Peyer's patches. Since Peyer's patches are known as major inductive sites of IgA-producing cells, we investigated the roles of Fc&[alpha]/&[mu]R in IgA production.
We found that Fc&[alpha]/&[mu]R-deficient mice showed elevated serum, but not fecal, IgA. Moreover, after oral administration of T- independent antigens, Fc&[alpha]/&[mu]R-deficient mice showed elevated antigen-specific serum, but not fecal, IgA production. Fc&[alpha]/&[mu]R-deficient mice showed comparable half life of serum IgA to wild type mice, indicating that the production of serum IgA is increased in Fc&[alpha]/&[mu]R-deficient mice. Indeed, IgA-positive B cells were increased in Peyer's patches, mecenteric lymph nodes and spleen in Fc&[alpha]/&[mu]R-deficient mice. Bone marrow chimeric mice demonstrated that serum IgA was elevated in mice whose non-hematopoietic, but not hematopoietic, cells lack Fc&[alpha]/&[mu]R expresssion. These results suggested that Fc&[alpha]/&[mu]R expressed on FDC in Peyer's patches may regulate IgA production against intragastrically administered antigens. The molecular and cellular basis of these phenomena are under investigation.
Immunomodulatory effects of dietary fibre supplementation on lymphocyte populations, cytokine and immunoglobulin A production(39.16)
Authors: Gannon Mark , Brooks Steve , Kalmokoff Martin , Raju Jayadev , Selinger Brent , Inglis Douglas , Green-Johnson Julia 
Published: January 2023

Abstract
Gastrointestinal microflora has been shown to have a bi-directional relationship with the host immune system. A variety of fermentable carbohydrate polymers largely pass through the small intestine, providing fermentable substrates for gut microflora. Dietary fibre supplementation may provide a strategy for manipulating the intestinal bacterial profile, changing the interaction with the mucosal immune system, thereby modulating the host immune system. Over a six week trial, 30 weanling BioBreeding rats were fed either control diet alone or supplemented with oat bran or wheat bran fibre. We have shown that wheat bran fibre increases mesenteric lymph node (MLN) B lymphocyte numbers, and decreases systemic IL4 production, MLN T lymphocytes, and intestinal IgA, concurrent with increased colonic bacterial population diversity. We also observed no evidence of pro-inflammatory responses resulting from dietary fibre supplementation. This lends support to the hypothesis that dietary fibre may modulate the host immune system through modification of the gut microflora profile.
The research is funded by the Advanced Foods and Materials Network
The role of TL1A-DR3 TNF-family interactions in inflammatory bowel disease (39.3)
Authors: Meylan Françoise , Song Yun-Jeong , Malm Ian , Acharya Krishika , Kahle Erin , Fuss Ivan , Strober Warren , Belkaid Yasmine , Siegel Richard 
Published: January 2023

Abstract
DR3 is a TNF-receptor specifically expressed on lymphocytes which can costimulate lymphocyte activation. Its ligand, TL1A, can be produced by at least 3 different cell subsets: endothelial cells, lymphocytes and DC. TL1A and DR3 have been reported to be upregulated in biopsy samples and in animal models of IBD, providing circumstantial evidence of the involvement of this TNF ligand-receptor pair in IBD. We have generated TL1A transgenic mice that constitutively express TL1A by either T-cells or DC. Both of these transgenic lines develop spontaneous IBD. Constitutive expression of TL1A by T cells leads to a severe pathology found primarily in the ileum and duodenum in all founders, from an early age. Consistent with the role of TL1A as a T cell costimulator, the T cell population had an activated phenotype and increased effector subsets. Surprisingly, despite the inflammation, we observed increased FoxP3+ cells. Interestingly, IL-13 and to a lesser extent IL-17 are the cytokine mRNA that are the most elevated in the gut. In contrast, constitutive expression of TL1A by DC leads to a milder pathology that is more restricted to the ileum, and is detectable in older mice. Ectopic expression of TL1A appears to be able to overcome T-cell self-tolerance and drive IBD with no other overt stimuli. These findings suggest that TL1A may be an interesting target for therapy.
Selection and application of M cell targeting peptide ligand to induce immune responses after mucosal immunization of the ligand-fused antigen (39.31)
Authors: Jang Yong-Suk , Kim Sae-Hae , Seo Ki-Weon , Lee Kyung-Yeol 
Published: January 2023

Abstract
Mucosa is the most successful application area of vaccination through the induction of the systemic and mucosal immune responses. In this study, we have searched for reliable peptides which could be used as mucosal adjuvant to potentiate the orally introduced antigen to induce the immune response. Using the phage display library, we have selected peptides which can bind onto cultured M cell model using Caco-2 and Raji co-culture system which had been confirmed by UEA-1, WGA, and M cell specific antibody by confocal scanning light microscopy. Interestingly, one of the selected peptides showed a high homology with outer membrane protein of Yersinia enterocolitica-like strains which are well-known human pathogen causing various gastrointestinal systemic syndromes and capable of invading and destroying M cells. In order to confirm the role of selected peptide to enhance the immune response induction after oral administration, fusion proteins between a peptide ligand and EGFP or VP1 antigen of foot-and-mouth disease were produced and tested in ex vivo intestinal loop and in vivo mouse systems. (This work was supported by the grant from ARPC.)
Retinoic acid as an adjuvant to imprint mucosal homing properties to vaccine-induced T cells (39.32)
Authors: Tan Xuefang , Blattman Joseph , Greenberg Phil 
Published: January 2023

Abstract
Objective: All-trans retinoic acid (ATRA) induces the expression of gut-homing receptors on T cells during activation in vitro. We investigated the effect of ATRA as an in vivo adjuvant during vaccination on the formation and migration of memory T cells.
Methods: T cells were analyzed in control and ATRA treated mice immunized with recombinant adenovirus expressing the LCMVgp33 epitope as well as following heterologous virus challenge. To directly compare the proliferative capacity and homing of memory cells from ATRA or vehicle-treated mice, these cells were co-transferred into recipients and responses analyzed following MVAgp33 challenge.
Results: ATRA treatment during priming resulted in increased memory T cells in mucosal tissues and somewhat decreased splenic memory CD8 T cells. T cells primed in the context of ATRA exposure mounted stronger responses to systemic challenge with MVAgp33, and were more resistant to challenge with VVgp33 at vaginal surfaces. In co-transfer experiments, memory CD8 T cells from ATRA treated mice exhibited greater proliferation and increased gut homing.
Conclusion: ATRA exposure during priming promotes the generation of memory T cells with greater proliferative potential and enhances mucosal localization. Thus ATRA may be a useful as an adjuvant during vaccination to enhance T cell responses at mucosal sites. This work is supported by the Bill & Melinda Gates Foundation.
Powerful mucosal immune response in macaques (Macaca mulatta) in response to SIV gp96-Ig immunization (39.35)
Authors: Strbo Natasa , Vaccari Monica , Pahwa Savita , Kolber Michael , Fisher Eva , Gonzalez Louis , Felber Barbara , Pavlakis George , Franchini Genoveffa , Podack Eckhard 
Published: January 2023

Abstract
Induction of mucosal immunity is critical for protection from enteric pathogens. We have developed a vaccine design that utilizes the unique property of the endoplasmic reticulum chaperon, heat shock protein (HSP) gp96, to bind antigenic peptides and deliver them to APCs.
The aim of our study was to evaluate safety and systemic and mucosal SIV-immunity with secreted gp96-Ig vaccines in non-human primates.
We have generated a secreted form gp96 by replacing the ER retention sequence KDEL with the IgG1-Fc tag. HEK-293 cells were transfected with gp96-Ig and with the cDNAs encoding the SIV antigens gag, pol, env and retanef (reassorted rev, tat, nef). Irradiated, transfected 293 cells that secrete 1, 5 or 50 micrograms gp96-Ig-SIV-peptide complexes in 24h, were injected intraperitoneally in Mamu-A*01+ macaques at 0, 4 and 24 weeks. The frequency of SIVGag- and SIVTat- tetramer+ cells in the rectal mucosa reached 30-50% in some macaques after the third immunization. Tetramer+ cells expressed appropriate functional (granzymeB) and migration markers (alpha4beta7, CD103). The cells secrete IL-2 and IFN-gamma in response to different peptide (gag, tat, env) stimulation.
We conclude that the cell secreted SIV-gp96-Ig vaccine is safe and can induce strong poly-specific, multifunctional CD8 responses in mucosal compartments that are thought to be critical for protection from SIV/HIV infection.
Neonatal Tolerization with Bacterial Antigens Stimulates an Expansion of CD11b+ Leukocytes with Inhibitory Activity in IL-10 Gene-Deficient Mice (39.38)
Authors: Sydora Beate C , Foshaug Rae R , Fedorak Richard N 
Published: January 2023

Abstract
Tolerance to antigens of the endogenous flora can be induced by intra-peritoneal injection of 100 microliter of a sterile lysate solution (2mg/ml protein) prepared from fecal material of conventionally-raised mice with enteric micro flora into neonates. In IL-10 gene-deficient mice this treatment results in delayed onset of intestinal inflammation and reduced levels of pro-inflammatory cytokine release with a concomitant increase in CD11b+ leukocytes in spleen. To investigate whether these CD11b+ leukocytes play an active role in the reduction of bacteria-induced immune responses we isolated CD11b+ leukocytes from spleens of 20 week old mice that were tolerized to bacterial antigens as neonates and added these cells in limited dilutions to spleen cell cultures stimulated with bacterial antigens.
We found that in bacterial antigen-tolerized, Il-10 gene-deficient mice the amount of CD11b+ leukocytes in spleen doubled compared to the amount found in untreated mice and mice injected with germ-free lysates. Sorted CD11b+ spleen cells from tolerized mice were able to inhibit antigen-stimulated spleen cell proliferation and release of pro-inflammatory cytokines in a concentration-dependent manner suggesting that CD11b+ cells play a regulatory role in the response to bacterial antigens in this IBD model. This work is supported by the Crohn's and Colitis Foundation of Canada.
Surfactant protein A differentially modulates the functional outcome of T cell activation (39.45)
Authors: Mukherjee Sambuddho , Giamberardino Charles , Evans Kathy S , Goto Hisatsugu , Pastva Amy , Lo Bernice , Wright Jo Rae 
Published: January 2023

Abstract
The pulmonary surfactant lipoprotein complex lowers the surface tension at the alveolar/airway interface of the lung and participates in pulmonary host defense. Previous studies have shown that surfactant protein A (SP-A) inhibits lymphocyte proliferation. We hypothesized that surfactant proteins may modulate the activation threshold of T cells depending upon the strength of the activation signal.
The strength and duration of lymphocyte activation are crucial in determining the fate of responding lymphocytes. Activation of specific signaling pathways, including NFkB, NFAT, STAT and MAPK pathways, determines the quality, magnitude and duration of immune responses, imparts a tunable quality, and essentially constitutes the 'strength of signal' (SoS). This study highlights a differential role of SP-A across multiple modes of T cell activation. Modulation of signal strength imparted by different activating agents ex vivo and in vivo in different mouse models, as well as in vitro with human cells show a strong correlation between strength of signal and functional effects of SP-A interactions. While proliferation is enhanced in the presence of SP-A at low signal strengths, the inhibition reported in the literature is observed at higher SoS. The enhanced proliferation is observed within a kinetic envelope, and is largely absent in SP-A-/- mice, while the inhibition is primarily caused by lack of cell cycle progression, with no effect on cell death or early cytokine production. This is intrinsic to the global T cell population, and is not mediated by proportions of Treg or effector memory cells. Changes in capacitative [Ca++]i flux are likely to be a key component of these phenotypic effects.
[Support: NIH HL-68072]