bluuebunny/crossref_metadata_2025_split huggingface dataset:
Reciprocal generation of Treg and Th1/Th17 cells by conventional B cells and B1 B cells (88.46)
Authors: Zhong Xuemei , Gao Wenda , Degauque Nicolas , Bai Chunyan , Kenny James , Lu Yan , Oukka Mohamed , Strom Terry B , Rothstein Thomas L 
Published: January 2023

Abstract
Regulatory T cells (Treg) are indispensable for maintaining peripheral tolerance, whereas Th1 and Th17 cells induce inflammation and tissue destruction. Here we report a novel regulatory role for B cell subsets in influencing the differentiation of Treg versus Th1/Th17 cells. Using Foxp3-GFP knock-in mouse, we demonstrated that conventional B cells excelled in converting Foxp3− CD4 T cells into Foxp3+ Treg cells in the presence of IL-2 and TGFβ, whereas under the same conditions, peritoneal B1 cells preferentially generated Th1 and Th17 cells. We also demonstrated that B1 B cells promote stronger T cell proliferation during antigen presentation and MLR as compared to conventional B cells. Costimulation blockade of CD86 but not CD80 partially reversed the poor Treg conversion by B1 cells. Hence the ability to convert Treg is inversely correlated with B cell antigen-presentation capacity. Our findings suggest that different B cell subsets can play distinct roles in immune regulation by polarizing T cell functions.
This study was supported by grants from the American Heart Association (0325807T), the Juvenile Diabetes Research Foundation (5-2006-19) and the National Institutes of Health (AI29690 and AI60896).
Crystal structure of SLAM family members: implications for their costimulatory functions in T cell (88.9)
Authors: Yan Qingrong , Malashkevich Vladimir , Cao Erhu , Lary Jeffrey W , Cole James L , Nathenson Stanley G , Almo Steven C 
Published: January 2023

Abstract
Members of the signaling lymphocyte activation molecule (SLAM) family, including homophilic and heterophilic receptors, modulate a wide range of immune responses, including T cell activation and NK-cell activation. The SLAM family members share a similar ectodomain organization, with an N-terminal IgV domain and a C-terminal IgC2 domain. The sole exception is the Ly-9 ectodomain, which is composed of a tandem repeat of the IgV-IgC2 motif. The homophilic interaction is mediated by the first N-terminal IgV domain. The 2.0 Å crystal structures of the CD84 and Ly9 first N-terminal IgV domains reveal a similarly organized homophilic interaction with the recently reported NTB-A homophilic interaction, the differences in the homophilic interfaces is likely an important mechanistic feature that prevents the formation of undesired heterodimers among the SLAM family receptors. Notably our biochemical data also indicated the strong self association of CD84 and Ly9 with a Kd in the sub-micromolar range. The fact that the homophilic affinities span over three orders of magnitude among the SLAM family members suggests that the difference in the affinities might be a contributor to the different signaling behaviour exhibited by the individual family members.
In Vitro Human Immune Response to Low Dose Mercury (89.11)
Authors: Gardner Renee Michelle , Nyland Jennifer F. , Evans Sean , Silbergeld Ellen K. 
Published: January 2023

Abstract
There is growing recognition that exposures to both inorganic and organic mercury (Hg) compounds can affect immune function, with potential consequences for host resistance to infections and risks of autoimmune disease. However, there is little information on human responses to low level Hg exposures. For this reason, we are investigating immune function using in vitro exposures to Hg in primary cultures of human peripheral blood mononuclear cells (PBMCs) from healthy adult volunteers. PBMCs were exposed to a concentration of HgCl2 up to 200 nM (which roughly corresponds to a whole blood concentration at the upper range of occupationally exposed or fish eating populations), in the presence and absence of activation by LPS. We found that these concentrations are non-cytotoxic and do not affect cell subsets or markers of cell activation. However, in PBMCs from both males and females, dose-dependent increases in both TNFα and IL-6 were observed in cell culture supernatants in the presence of LPS. No changes were observed in IFNγ, IL-4, IL-5, or IL-13 levels. No changes were seen in any cytokine in the absence of LPS. The results indicate that Hg can exert significant effects on signal transduction pathways in human cells in vitro, at exposures that are non-cytotoxic and environmentally relevant.
A novel inhibitory peptide of Toll-like receptor signaling limits LPS-induced production of inflammatory mediators and enhances survival in mice (89.12)
Authors: Hefeneider Steven H , McCoy Sharon L , Billiar Timothy R , Tsung Allan 
Published: January 2023

Abstract
Sepsis resulting from gram-negative bacterial infections is characterized by an excessive inflammatory immune response initiated by exposure of the host innate immune system to either bacteria or bacterial products, primarily LPS. Engagement of the TLR4 receptor on immune cells by LPS induces production of inflammatory mediators leading to tissue damage. We recently identified a peptide, termed P13, which was previously shown to be a potent inhibitor of in vitro TLR-signaling. In this study, we demonstrate that use of this novel peptide significantly reduces the in vitro production of inflammatory mediators seen after exposure of hepatocytes/NPC co-cultures and endothelial cells to LPS. In addition, in vivo treatment of mice with this peptide was effective at inhibiting LPS-induced production of inflammatory mediators and significantly limited liver damage. Peptide treatment significantly increased survival of LPS/D-galactosamine treated mice and mice treated with high dose LPS. These results demonstrate the therapeutic potential of peptide P13 to limit an LPS-induced inflammatory response and enhance survival in models of inflammation.
This study was supported by NIH SBIR 1R43AI065000-01A1
Novel mutations in CRAC channel protein Orai1 cause immunodeficiency associated with non-immunological disease (89.23)
Authors: Feske Stefan , Osmers Ute , Kirschner Janbernd , Roether Jens , Picard Capucine , Ehl Stephan , Plogmann Katrin , Fischer Alain , Rao Anjana 
Published: January 2023

Abstract
Orai1 has recently been identified as a pore subunit of the Ca2+ release activated Ca2+ (CRAC) channel essential for the function of T lymphocytes, mast cells and other cells types. A point mutation in Orai1 abrogates CRAC channel function and causes Severe Combined Immunodeficiency (SCID) in human infants. We here report that the immunodeficiency is accompanied by hypohidrotic ectodermal dysplasia (HED) and congenital myopathy, characterized by absent sweat production, dysplastic dental enamel, non-progressive muscle weakness and histologically a predominance of type I and atrophic type II mucle fibers. A major defect in the activation of NF-kB, known to cause HED accompanied by immune deficiency in patients with mutations in IkBα or IKKγ, was ruled out, although a partial, Ca2+ dependent impairment of NF-kB activation downstream of TCR crosslinking was observed. An novel nonsense mutation in Orai1 was observed in an unrelated SCID patient causing a premature truncation of Orai1 protein. The resulting lack of Ca2+ influx and CRAC channel activity could be rescued by ectopic expression of Orai1 in the patient’s cells. The immunodeficiency in this patient is accompanied by fatal progressive growth retardation and encephalopathy, but HED and myopathy are absent. These clinical phenotypes indicate that Orai1 may not only be necessary for regulating Ca2+ influx in the immune system but also several other tissues.
Chemokine receptor signaling in mast cells (89.27)
Authors: Aye Cho Cho , Ono Santa 
Published: January 2023

Abstract
Mast cells play an important role in IgE-associated allergic disorders and immune response to parasites.
In a former study, we demonstrated that chemokine CCL3 (MIP-1α) acted as a co-stimulator for FcεRI-mediated activation on mast cells. To advance our understanding on this finding, we studied gene profiles in Rat Basophilic Leukaemia mast cells after co-activation of CCR1 (a receptor of CCL3) and FcεRI using the Affymetrix GeneChip Arrays. Emp1 (Epithelial Membrane protein 1), RT1-S3 (non-classical type 1 MHC gene), and Slc35e4 (solute carrier family 35, member E4) were found to be the top possible synergy-related genes. Validations of this data are being carried out using real time PCR, western-blotting and siRNA technologies.
Further to our in vivo findings of the inhibition of the immediate hypersensitivity reactions in the conjunctiva and the attenuation of mast cell degranulation in MIP-1α deficient mice, we would like to check if MIP-1α and CCR1 play a critical role to produce these effects. We reconstituted the bone marrow-derived mice mast cells (BMMC) from naïve mice into mast cell-deficient mice and confirmed that the reconstituted BMMC home to their eye. The next step is to examine whether CCR1 and CCL3 are critical for mast cell activation and allergic conjunctivitis-like symptoms following induction of murine allergic conjunctivitis using CCR1- and CCL3- deficient mice.
Modeling GRB2 and SOS1-mediated Oligomerization of LAT: The Role of Valence Switching (89.30)
Authors: Faeder James R , Nag Ambarish , Goldstein Byron 
Published: January 2023

Abstract
Ligand-induced receptor aggregation is a well-known mechanism for the initiation of intracellular signals, but recent evidence also indicates that oligomerization of distal signaling molecules may be required for signal propagation. Formation of signaling complexes containing oligomers of the transmembrane adaptor protein LAT has recently been identified as a critical step in TCR-mediated signaling [Houtman et al., Nat Struct Mol Biol, 13, 798 (2006)]. Cross-linking of LAT arises from the formation of a 2:1 complex between GRB2 and SOS1, which bridges two LAT molecules through the interaction of an SH2 domain on each GRB2 with a phosphotyrosine of each LAT. We have developed a mathematical model to describe this oligomerization and determined the distribution of LAT oligomers and the kinetics of oligomer formation, which we compare with recent experimental results. The valence of LAT for binding GRB2, i.e., the number of LAT phosphotyrosines that can bind the GRB2 SH2 domain, ranges from 0 to 3 and is a critical factor in determining both the nature and extent of aggregation. A dramatic rise in oligomerization occurs between valence 2 and 3, a phenomenon we call valence switching because the valence is controlled by the extent of phosphorylation of specific LAT tyrosines.
Supported by grant R37 GM35556 from the National Institutes of Health and the Department of Energy through contract DE-AC52-06NA25396.
Signaling pathways involved in foreign antigen expression by a recombinant vaccinia virus (89.38)
Authors: Hu Ningjie , Shikuma Cecilia , Shiramizu Bruce , Koo Raymond , Yewdell Jonathan W 
Published: January 2023

Abstract
BACKGROUND: Vaccinia virus (VV) was used as a live vaccine to eradicate smallpox and has in recent years received considerable attention for the development of live vaccine vectors due to its broad host range and ability to express a variety of foreign antigens, which can induce humoral and cellular immunity against virus infections. However, little is known about the cellular signaling pathways involved in the foreign antigen expression by a recombinant VV.
METHODS: Using a recombinant EGFP-VV, we studied four cellular signaling pathways, PI3K, p38 MAPK, JNK, and ERK, by assessing EGFP production in infected human peripheral blood monocytes and monocyte-derived dendritic cells (MDDCs).
RESULTS: EGFP expression was inhibited significantly in both monocytes and MDDCs infected with EGFP-VV by blocking the PI3K, p38 MAKP, and JNK pathways by specific inhibitors LY294002, SB203580, and SP600125, respectively. PI3K was the most critical pathway involved in antigen expression by VV-infected cells, whereby LY294002 (25 uM) exhibited 90.1% decrease of EGFP expression compared to non-inhibitor-treated control (DMSO). Whereas, at the same concentration (25 uM), SB203580 and SP600125 inhibited only 69.3% and 30.4% of EGFP expression, respectively. Inhibition of the ERK pathway by PD098059 did not alter EGFP expression.
CONCLUSIONS: VV is able to infect APCs and efficiently express inserted gene(s) through cellular signaling pathways of PI3K, p38 MAPK, and JNK, but not ERK.
ACKNOWLEDGMENTS: This work was supported by University of Washington CFAR (Award AI 27757), Hawaii Community Foundation (Award 20061466), UH INBRE, and HACTU grant from NIAID (A134853).
Regulation of CD1d expression by vitamin D results in fewer hyporesponsive iNKT cells in the vitamin D receptor knockout mouse. (89.7)
Authors: Yu Sanhong , Cantorna Margherita T 
Published: January 2023

Abstract
CD1d-reactive natural killer T (NKT) cells with an invariant T cell receptor Vα14 rearrangement (i) are a unique subset of lymphocytes, which play important roles in immune regulation, tumor surveillance and host defense against pathogens. Vitamin D and the vitamin D receptor (VDR) are important regulators of T cell function, yet their role in iNKT cells remains unknown. Expression of the vitamin D receptor (VDR) is required for normal development of iNKT cells. Mice lacking the VDR had significantly fewer iNKT cells and the remaining iNKT cells were hyporesponsive. iNKT cell development is blocked at a late stage in iNKT cell development, the CD44high NK1.1− stage. Bone marrow transplantation showed that VDR knockout (KO) hematopoetic cells fail to repopulate iNKT cells in the wild type thymus. The block was not due to fewer iNKT precursors in the VDR KO mice but instead CD1d expression was diminished in the VDR KO thymus. The decreased CD1d results in fewer, hyporesponsive iNKT cells in the VDR KO mouse. The data suggest that vitamin D through the vitamin D receptor is critical for proper iNKT cell development and function.
The Immunomodulatory Effects of Ascaris suum Pseudocoelomic Fluid in Th1-Mediated Systems (90.10)
Authors: Hodges Marcus Gomez , Smith Allen , Urban Joseph , Keane-Myers Andrea 
Published: January 2023

Abstract
Recent studies found that adoptive transfer of helminth-primed dendritic cells impairs host protection to the enteric pathogen, Citrobacter rodentium. In the present study, we used Ascaris suum pseudocoelomic fluid (PCF) in lieu of infection, and demonstrated that pre-exposure of bone-marrow derived dendritic cells to PCF, prior to LPS stimulation, suppressed activation marker expression and production of IL-12. Similar to LPS, heat-inactivated and extract preparations of C. rodentium induced dendritic cell activation. This activation was suppressed in cells previously exposed to PCF, resulting in decreased expression of CD40, CD86, and MHC II. These findings suggest that PCF may modify Th1 responses in the host. In preliminary studies, BALB/c mice were sensitized with PCF (100 μg), followed by oral inoculation with C. rodentium (2.5 x 108 CFU). Bacterial colonization and colonic hyperplasia was assessed at days 3 and 7 post-infection. Mice receiving two sensitizations prior to inoculation had increased C. rodentium colonization in the cecum and colon by day 7 post-infection, compared to those receiving no pre-treatment. We are currently repeating this experiment using a higher concentration of PCF (200 μg) to enhance differences in bacterial colonization. This model may help determine if PCF alters the course of Th1-mediated immunoregulation in allergic inflammatory responses.
Synergistic effect of TNF-α and ceramide on the production of IL-8 in A549 cells and A549 cells transfected with human ceramide kinase (CERK). (90.11)
Authors: Hinkovska-Galcheva Vania , Van Way Susan M , Cornell Timothy , Sun Lei , Gueorguieva Iana , Zlatarov Nikolay 
Published: January 2023

Abstract
Many inducers of the stress response result in ceramide (Cer) accumulation as a result of activation of either sphingolyelinases (SMases) or the de novo pathway. Recently, there is strong evidence for a role of sphingolipids in inflammatory responses such as leukocyte recruitment. The attraction of leukocytes to tissues is essential for inflammation and the host response to infection. Following stimulation by TNF-?, the production of IL-8 increased over time in a concentration dependent manner. Simultaneously, Cer levels increased gradually from 7.56 % during 15 minute stimulation to 35% for 16 hour stimulation. Using Fumonisin B1, an inhibitor of de novo synthesis of Cer, which inhibits Cer synthesis by 25%, we observed 17% decrease of IL-8 expression. When the inhibitor for neutral (SMase) GW4869 was used on A549 cells, there was a significant reduction of Cer as well as IL-8. Subsequently, two serine-threonine phosphatases (PPas), protein phosphatase-1 (PP1) and protein phosphatase-2A (PP2A) have been shown to be Cer responsive in vitro and in vivo. These results suggest that TNF-? stimulates the production of IL-8 by a mechanism that involves the sphingomyelin-Cer system. Cer may be important in increasing the production of IL-8 in A 549 cells. Since Cer can be phosphorylated by CERK to C1P, we predict that CERK expression may affect the balance between these sphingolipids and influence the Cer dependent PPas.
Cyclic patterns of respiratory burst activity in zebrafish (Danio rerio) (90.12)
Authors: Hannum Lynn , Kaplan Jessica 
Published: January 2023

Abstract
The cyclic expression of clock genes creates daily variations in physiology, including immune system components. To investigate circadian patterns of immune function in zebrafish, we have focused on respiratory burst activity in phagocytic cells from kidney, the principal lymphoid organ in fish. Respiratory burst responses were assayed at four hour intervals using 2’,7’-dichlorofluorescein diacetate (H2DCFDA) to indicate reactive oxygen species (ROS) levels. We initially stimulated cells with phorbol 12-myristate 13-acetate (PMA). While responses to PMA did not vary throughout the day, the levels of ROS in control cells varied significantly peaking prior to dawn, followed by a low several hours later. Next, we analyzed responses to stimulation with zymosan A. The relative increase in ROS production after exposure to zymosan varied daily, being highest daily at 2 AM, with a low at 10 PM. Interestingly, the kinetics of the response to zymosan varied throughout 24-hour periods as well; it took significantly longer to reach the peak production of ROS when cells were stimulated with zymosan at 6 AM than at 10 PM, which had the shortest time to peak response. Our data highlight the potential of zebrafish as a model of circadian control of immune function in vertebrates.
This work was supported by NIH Grant Number P20 RR-016463 from the INBRE Program of the National Center for Research Resources.
Estrogen augments the number and activity of CD11c+CD49b+NK1.1int cells in vivo (90.4)
Authors: Siracusa Mark , Overstreet Mike , Scott Alan L , Klein Sabra L 
Published: January 2023

Abstract
Estrogens may increase innate immune responses, which may augment subsequent adaptive responses and lead to female-biased resistance to infection. Both dendritic cells (DCs) and natural killer (NK) cells are key players in innate immunity; thus, the goal of the present study was to test the hypothesis that the functioning of DCs and NK cells is affected by exposure to 17β-estradiol (E2) via estrogen receptors. To test whether E2 alters the number, phenotype, or function of mature cells, CD11c+ DCs and NK cells were isolated from the spleens of female C57BL/6 mice that were intact, ovariectomized, or ovariectomized with E2 replaced exogenously. Neither removal nor replacement of E2 affected the number of CD11c+CD11b+ cells in the spleen. E2 did not affect the expression of MHCII, B220, CD8α, CD40, or CD86 on monocytes. The presence of E2 increased the number of CD11c+CD49b+NK1.1int cells, but reduced numbers of CD11c+CD49b+NK1.1hi cells, which also were B220+, CD49b+, and Gr1-, a phenotype reported for interferon-producing killer DCs (IKDCs). CD11c+CD49b+NK1.1int cells expressed MHC II, CD40, CD11b, B220, and CD8α. E2 did not affect the lytic activity of CD11c+ cells. CD11c+ cells produced more IFNγ, but neither IL-12 nor IFNα, in the presence of E2. In vitro, E2 facilitated differentiation of bone marrow precursor cells into functional CD11c+ DCs and increased the expression of CD11b, MHCII, CD40, and CD86, but not NK1.1 or CD49b. These data provide in vivo evidence that E2 differentially affects distinct populations and functions of CD11c+ cells.
Support: NIH grant AI054995 and JHMRI pilot award
Atractylodes japonica enhances CD4+ T-cell activities and modulates Th1/Th2 differentiation (90.8)
Authors: Lee hee kyung , Bae Hyunsu , park namhee 
Published: January 2023

Abstract
Atractylodes japonica (AJ) is a common used herbal medicine in Asian countries such as Korea, China and Japan. The present study was designated to evaluate the direct effects of AJ on helper T cell activities and on Th1/Th2 lineage development in vitro. The results demonstrated that AJ had no mitogenic effects on unstimulated CD4+ T cells, but augmented CD4+ T-cell proliferation upon activation with anti-CD3/anti-CD28 antibodies in a dose-dependent manner. AJ treatment significantly increased CD4+T cell population and the IFN-γ expression was significantly enhanced, while IL-4 expression was significantly decreased. In addition, in vitro Th1/Th2 polarization experiments revealed that AJ enhanced IFN-γ secretion in Th1 cells, but reduced the IL-4 in Th2 cells in dose-dependent manner.
Therefore, these results suggest that AJ treatment could be a desirable alternative therapy for the prevention or correction of Th2 dominant pathological disorders, such as allergy and asthma.
TCR- independent induction of IL-17 production in TH17 Cells (91.11)
Authors: Lee Yun Kyung , Weaver Casey T. 
Published: January 2023

Abstract
Effector CD4 T cells have been classically divided into two lineages, T-helper type 1 (TH1) and TH2. TH1 cells develop in response to intracellular viruses and bacteria and secrete interferon-γ (IFNγ) while TH2 cells produce interleukin (IL)-4 in response to extracellular pathogens. Recent studies have identified a third distinct lineage of effector CD4 T cells called as TH17 that characteristically produce IL-17. The development of TH17 cells depends on TGFβ and IL-6. The published reports establish a direct link between IL-23 and the TH17 cell subset in mediating inflammatory pathology in certain autoimmune diseases although IL-23 is not required for TH17 commitment. We observed that IL-23 acts synergistically with IL-1 or IL-18 to induce IL-17 cytokine production in TH17 cells independent of T cell receptor (TCR) stimulation, analogous to the induction of IFNγ by IL-12 and IL-18 in TH1 cells. Our results suggest that IL-1 or IL-18 signaling might be preceded by IL-23 signaling through the IL-23 receptor (IL-23R), which is upregulated in TH17 by TGFβ. The TH17 effector function is augmented by these non-antigen-specific responses subsequent to their previous antigen-induced differentiation. Our findings help to delineate the role of IL-23 in TH17 cell biology and identify potential targets for prevention of TH17-mediated immunopathology.
This work is supported by the National Institutes of Health (C.T.W.).