bluuebunny/crossref_metadata_2025_split huggingface dataset:
COX-2 inhibition represses the generation of M2 macrophages and slows tumor progression (111.31)
Authors: Ho Victor , Rauh Michael , Krystal Gerald 
Published: January 2023

Abstract
Macrophages (mΦs) are very heterogeneous and include immune-activating (M1) and immune-suppressive (M2) subsets. In response to cytokine or TLR activation, M1-mΦs (killer mΦs) express iNOS, which produces tumoricidal and bacteriocidal nitric oxide (NO). M2-mΦs (healer mΦs), in contrast, express arginase I, which competes with iNOS for L-arginine, to promote cell proliferation and fibrosis. SHIP (SH2-containing inositol-5’ phosphatase), a hematopoietic-specific negative regulator of the PI3K pathway, prevents M2-mΦ development. Thus, in SHIP-/- C57BL/6 mice, all the mΦs are M2 skewed. As a result, subcutaneously injected Lewis lung carcinoma (LLC) tumors grow faster in SHIP-/- than in +/+ mice, and this rapid tumor growth correlates with high tumor-associated arginase. We therefore hypothesize that high PI3K activity skews bone marrow (bm) progenitors to become tumor-promoting M2-mΦs. Herein we show that PGE2 also skews SHIP-/- , but not +/+, bm progenitors to M2 mΦs and that COX-2 inhibitors repress this skewing. Specifically, the COX-2 inhibitor SC-58125 reduces arginase levels and IL-10 production from in vitro derived SHIP-/- bmmΦs. Furthermore, another COX-2 inhibitor, Celebrex, slows tumor growth in vivo, and this correlates with reduced arginase in tumor-associated mΦs. This is consistent with COX-2 inhibitors slowing tumor growth, at least in part, by preventing M2-skewing of tumor-associated mΦs.
Actions of novel inflammation-resolving lipid mediators on human B cells (112.12)
Authors: Ramon Sesquile , Serhan Charles , Phipps Richard 
Published: January 2023

Abstract
The resolution of inflammation is an active and dynamic process. Newly identified lipid mediators are now recognized as key players during the process of inflammation resolution. These lipid-derived molecules constitute four families of endogenous mediators (lipoxins, resolvins, protectins and maresins) derived from essential fatty acids. New findings also demonstrated that these lipid mediators regulate aspects of the immune response, including inhibition of neutrophil infiltration, reduction of T cell cytokine production and stimulation of macrophage phagocytic activity. Their actions on B lymphocytes are not known. Our results indicate that the lipoxin B4 and 17-HDHA, used at 100nM, increase the ability of normal human B cells to produce IgM and IgG when activated with CpG plus anti-IgM. The two lipid mediators also enhance B cell differentiation towards antibody secreting cells. In addition, resolvin D1 and aspirin-triggered resolvin increase antibody production in CpG-stimulated B cells. None of these inflammation resolution lipid mediators affect proliferation and are non-toxic to B cells. Increase of plasma cell differentiation and antibody production coincides with the known involvement of pro-resolving mediators during the late stages of inflammation and pathogen clearance.
LFA-1 (CD11a/CD18) is required for T-cell homing to the mesenteric lymph nodes and gut but not for T-cell activation during the induction of chronic colitis (112.19)
Authors: Koboziev Iurii , Ostanin Dmitry , Gray Laura , Jackson Sherry , Kosloski-Davidson Melissa , Grisham Matthew 
Published: January 2023

Abstract
We have demonstrated that adoptive transfer of naïve LFA-1-deficient (CD11a-/-) T-cells into RAG-1-/- mice fails to induce chronic colitis whereas transfer of wild type T-cells induces chronic and unrelenting colonic inflammation. The objective of this study was to define the role that LFA-1 plays in T-cell activation and trafficking during the induction of chronic colitis in RAG-1-/- mice. In the first series of studies, we found that enteric antigen (EAg)-pulsed dendritic cells (DCs) induced a concentration-dependent increase in wild type (WT) and CD11a-/- CD4+ T-cell proliferation that was quantitatively very similar between the two groups whether we used bone marrow- or spleen-derived DCs, suggesting that LFA-1 is not critical for EAg-induced activation of T-cells in vitro. Short term trafficking studies (&lt;24 hrs) revealed a major defect in the accumulation of CD11a-/- T-cells within the MLNs compared to WT T-cells. When the observation period was extended to 3 and 7 days post T-cell transfer, we observed approximately 2-3-fold more WT T-cells within the MLNs and colon than CD11a-/- T-cells however, cell analysis revealed similar losses of CFSE fluorescence in both the WT vs. CD11a-/- T-cells suggesting that both populations of T-cells proliferated to same extent in vivo. Taken together, our data suggest that LFA-1 is important for T-cell trafficking to the MLNs and colon but is not required for EAg-induced T-cell activation in vitro or in vivo.
R-spondins protect from ischemia/reperfusion-induced tissue damage (112.25)
Authors: Kannan Lakshmi , Kis-Toth Katalin , Yoshiya Kazuhisa , Thai To-Ha , Tsokos George 
Published: January 2023

Abstract
Local and systemic inflammatory responses triggered by ischemia/reperfusion (IR) represent a leading cause of morbidity and mortality in a number of clinical settings including shock and transplantation. R-Spondins play a key role in wound healing and tissue regeneration through the modulation of the wnt pathway. We hypothesized that R-Spondins could prevent tissue injury caused by mesenteric IR by decreasing the local inflammatory response to ischemia. C57BL/6J mice were pretreated with vehicle or R-Spondins before inducing intestinal IR by clamping the superior mesenteric artery for 30 min. After this period of occlusion, the clamps were removed and the intestine was reperfused for 180 min. Intestinal injury was quantified by histologic scoring. Treatment with R-Spondins significantly decreased local intestinal injury. mRNA and protein analyses revealed that this effect was achieved through the modulation of the expression of inflammatory cytokines. Specifically, R-Spondins suppressed the levels of the IR-enhanced IL-6, IL-1β, TNFα, IL-10/CCL2 and CXCL5 cytokines/chemokines. Our results demonstrate that R-Spondins can mitigate the IR-induced local tissue damage induced by decreasing the local inflammatory cytokine response to ischemia and imply that they may be useful in the prevention of IR-related tissue damage.
The actin-bundling protein L-plastin is required for marginal zone B cell development (112.4)
Authors: Morley Sharon Celeste , Davis Chris , Muenzer Jared , Todd Elizabeth 
Published: January 2023

Abstract
B cell development is exquisitely sensitive to location within specialized niches in the bone marrow and spleen. Location within these niches is carefully orchestrated through chemotactic and adhesive cues. Here we demonstrate the requirement for the actin-bundling protein L-plastin (LPL) in B cell motility towards the chemokines CXCL12 and CXCL13, chemokines that guide normal B cell development. Impaired motility of B cells in LPL-/- mice correlated with diminished splenic maturation of B cells, with a profound (&gt;80%) loss of marginal zone B cells. Entry of LPL-/- B cells into lymph nodes and bone marrow was also impaired. Furthermore, LPL was required for the integrin-mediated enhancement of transwell migration but was dispensable for integrin-mediated lymphocyte adhesion. These results suggest that LPL participates in signaling that enables lymphocyte transmigration. In support of this hypothesis, the phosphorylation of Pyk-2, a tyrosine kinase that integrates chemotactic and adhesive cues, is diminshed in LPL-/- B cells. Furthermore, a well-characterized role of marginal zone B cells is the generation of a rapid humoral response to polysaccharide antigens. LPL-/- mice exhibited a defective antibody response to Streptococcus pneumoniae, and LPL-/- mice succumb rapidly to intra-tracheal infection with Streptococcus pneumoniae. LPL is thus critical for effective immunity against a significant human pathogen.
Interaction of α9 integrin on medullary sinus with its ligand regulates lymphocyte egress via regulating S1P transporter, Spns2 expression and subsequent S1P secretion under inflammatory condition (112.5)
Authors: Ito Koyu , Matsui Yutaka , Kurotaki Daisuke , Morimoto Junko , Kihara Akio , Uede Toshimitsu 
Published: January 2023

Abstract
Sphingosine 1-phosphate (S1P) is essential for lymphocyte egress from lymph node (LN). Despite its importance, it remains unclear how synthesis and secretion of S1P are regulated in LN. Here we report that α9 integrin is expressed on lymphatic endothelial cells (LEC) of medullary sinus in draining LN (dLN). In addition, Tenascin-C (TN-C), one of the α9 integrin ligands, was co-localized with LEC. The stimulation of LEC by TN-C in vitro led to the enhanced secretion of S1P. This α9 integrin-mediated enhancement of S1P secretion was not due to the augmentation of S1P synthesis, but rather induction of S1P transporter, Spns2. Abrogation of α9 integrin-mediated signaling by blocking anti-α9 integrin antibody (55A2C) in vivo resulted in the inhibition of lymphocyte egress from dLN under inflamed condition. Importantly, treatment of 55A2C did not affect lymphocyte egress under naive condition, indicating that blocking of α9 integrin-mediated signaling does not affect lymphocytes egress under non-inflammed condition. Consistent with those data, 55A2C attenuated severity of experimental autoimmune encephalomyelitis (EAE) with concomitantly accumulation of CD4+ T cell in dLN. Thus we propose that lymphocyte egress is regulated by α9 integrin-mediated signaling on LEC via inducing secretion of S1P from LEC under inflamed condition and that manipulation of α9 integrin-mediated signaling can be a potential therapeutic means for various inflammatory disorders.
Transcriptional profile of CD28 costimulation and Dec1 relevance in T-cell activation (113.14)
Authors: Martinez-Llordella Marc , Esensten Jonathan , Bluestone Jeffrey 
Published: January 2023

Abstract
Antigen recognition by the T cell receptor and costimulatory signal through CD28 receptor are required for a complete T-cell activation. CD28 ligation regulates a wide range of biochemical processes that drive T-cell proliferation, prevent apoptosis and enhance IL-2 production. However, the direct effect of CD28 signaling on the global gene transcription after T-cell activation remains controversial. We described the transcriptional profile of CD28 costimulation employing microarray analysis of human naïve CD4+ T cells. Although we demonstrated that CD28-dependent signaling had quantitative effects on gene expression during the first stages of activation, strong qualitative changes on transcription were observed by 24 hours after activation. Among the genes directly induced by CD28 costimulation we identified the transcription factor Dec1. We described the critical role of Dec1 for the transcriptional response to CD28 costimulation in both Jurkat T cells and primary mouse CD4+ T cells. Importantly, we showed that the effects of Dec1 deficiency impact specifically on CD28 costimulation-dependent gene expression. Further, we proved that Dec1 is necessary to induce experimental autoimmune encephalitis in mice after MOG peptide immunization. This observation validates the in vivo importance of Dec1 for immune system function in a CD28-dependent disease.
Regulation of naïve T cell tolerance and regulatory T cell function by GRAIL (113.21)
Authors: Nurieva Roza , Lozano Guillermina , Dong Chen 
Published: January 2023

Abstract
CD4+ T cells are the master regulators of adaptive immune responses, and many autoimmune diseases arise due to a breakdown of self tolerance in CD4+ cells. Gene related to anergy in lymphocytes (GRAIL), the E3 ubiqutine ligase, has acknowledged as one of key molecules implicated in T cell activation and tolerance. In order to understand the physiological function of GRAIL in immune regulation, we have generated and analyzed GRAIL deficient mice. Naive T cells lacking GRAIL showed greatly enhanced proliferation and cytokine production after T cell receptor (TcR) activation. In addition, lack of GRAIL abrogated suppressive function of regulatory T (Treg) cells. We found that GRAIL deficient naive and Treg cells after TcR activation expressed substantially higher amounts of NFATc1 compared to wild-type cells, whereas the activation of other factors in AP-1 and NFκB pathways were normal. Our data also suggested that sustained TcR cell-surface expression in the absence of GRAIL led to selective NFATc1 expression in both naive T cells and Treg cells. In contrast to naïve T cells, GRAIL, through controlling NFATc1 expression, inhibits IL-21 production and upregulation of Th17-specific genes in Treg cells. Thus, the immune regulation by GRAIL in both naive and Treg cells is absolutely critical as evidenced by the failure of T cell tolerance induction and greatly increased susceptibility to autoimmune diseases of GRAIL deficient mice.
TCR-actin association mediated via unique motifs within the ζ-chain plays a central role in T cell activation (113.24)
Authors: Klieger Yair , Wang Lynn Wang , Almogi-Hazan Osnat , Baniyash Michal 
Published: January 2023

Abstract
Cytoskeleton rearrangement initiated upon specific T cell-antigen presenting cell (APC) interactions, is required for immunological synapse (IS) formation/maintenance, T cell activation and polar cytokine secretion. Following activation, most T cell antigen receptors (TCRs) are internalized and degraded though some long-lived T cell-APC conjugates are maintained, by a yet unknown mechanism. T cells express at least two TCR forms, non-cytoskeleton (non-cska) and cytoskeleton (cska) associated; the latter are linked to actin via the ζ-chain. However, the mode of association and the functional significance of the cska-TCRs are currently enigmatic. We discovered two positively charged motifs within the ζ-chain intracytoplasmic region mediating its binding to F-actin and inducing actin bundling. T cells expressing ζ-chain mutated in these motifs, although displaying normal levels of cell surface TCRs and some immediate signaling events, they are devoid of cska-TCRs and are unable to present activation-dependent TCR cap formation, IS establishment and cytokine production/secretion. Accordingly, we demonstrate that APCs also display abnormal activation patterns. Based on the cumulative data showing that T cells expressing mutated ζ-chain are unable to display cellular events critical for the execution of an optimal immune response, we propose a model for the key roles of the cska-TCRs in TCR-mediated activation.
Anti-CD8 antibodies can trigger T-cell effector function in the absence of TCR engagement and improve pMHCI tetramer staining (113.28)
Authors: Wooldridge Linda , Ladell Kristin , Price David , Sewell Andrew , Clement Mathew 
Published: January 2023

Abstract
Cytotoxic T lymphocytes (CTLs) recognize foreign peptides presented at the cell surface bound to major histocompatibility complex class I (MHCI) molecules. Antigen recognition involves the binding of both T-cell receptor (TCR) and CD8 co-receptor to the same peptide-MHCI (pMHCI) ligand. Specificity is determined by the TCR, whereas CD8 mediates an effect on antigen sensitivity. Anti-CD8 antibodies have been used extensively in previous studies to examine the role of CD8 in CTL activation. However, it is unclear from the literature whether anti-CD8 antibodies per se are capable of inducing effector function. Here, we report on the ability of seven monoclonal anti-human CD8 antibodies to activate six human CTL clones with a total of five different specificities. Six out of seven anti-human CD8 antibodies tested did not activate CTLs. In contrast, one anti-human CD8 antibody, OKT8, induced effector function in all CTLs examined. Moreover, OKT8 was found to enhance TCR/pMHCI on-rates and, as a consequence, could be used to improve pMHCI tetramer staining. The observed heterogeneity in the ability of anti-CD8 antibodies to trigger T-cell effector function provides an explanation for the apparent incongruity observed in previous studies and should be taken into consideration when interpreting results generated with these reagents. Furthermore, the ability of antibody-mediated CD8 engagement to deliver an activation signal underscores the importance of CD8 in CTL signalling.
Differential expression of IL-17A and Il-17F in inflammatory bowel disease/colon cancer using a new IL-17A/F-dual-color reporter mouse (114.1)
Authors: Shen Wei , Li Wenqing , Feigenbaum Lionel , Hixon Julie , Durum Scott 
Published: January 2023

Abstract
Interleukin (IL) 17A and IL-17F are products of Th17 cells which are associated with autoimmunity and many inflammatory diseases such as rheumatoid arthritis and inflammatory bowel disease. Some studies have suggested that production and activity of these two cytokines may be different and we sought to visualize them simultaneously in the inflamed bowel. A bacterial artificial chromosome was modified to introduce two fluorescent reporter genes, tdTomato and GFP, into the linked IL-17A and IL-17F genes respectively. Mice were generated that harbor the BAC construct. In vitro, splenic T cells cultured under Th17 conditions showed single expressing cells and dual expressing cells. In vivo colonic intraepithelial cells in DSS-induced acute mouse colitis showed slightly more IL-17A reporter than IL-17F, while in AOM/DSS induced chronic mouse colitis model, much more IL-17A reporter than IL-17F was expressed. In the T cell (CD4+CD45RBhigh) transfer colitis model, only expression of the IL-17A reporter could be detected in intestinal intraepithelial cells of Rag1-/- recipients. These IL-17A/F-dual-color reporter mice should prove useful in determining the sites of microenvironmental triggers of activation of Th17 cells and other cells that produce IL-17A and F.
Phenotypic and functional differences in Foxp3+ cells expressing different levels of the IL-2 receptor α-chain CD25 (115.20)
Authors: Brand David , Luo Jiwen 
Published: January 2023

Abstract
Regulatory T cells (Tregs) are key players in tolerance and immune homeostasis. The identification of this unique cell subset was originally established through identification of CD4+ T cells expressing high levels of the IL-2 receptor α-chain CD25. CD4+CD25+ cells from naïve mice are predominantly Tregs. CD4+CD25- cells are predominantly conventional T cells. With the identification of the nuclear transcription factor Foxp3 as a protein that plays a key role in the biology of Tregs and with GFP as a means of selection, pure populations of Foxp3 expressing cells can be obtained. Among murine CD4+ T cells that express Foxp3, there is a continuum of CD25 expression from negative (or very dim) to very bright. Our analyses of peripheral Foxp3+CD4+CD25dim/- cells suggest that while their transcription of many cytokine, chemokine and receptor genes are similar to Foxp3+CD4+CD25bright T cells, they do not have identical phenotypic and functional properties, with the latter capable of a greater degree of suppression and an enhanced transcription of Interleukin-7. Parenteral administration of a heterologous type II collagen to induce tolerance in a TcR tg mouse model of Collagen-Induced Arthritis increases the percentage of Foxp3+CD4+CD25bright T cells and protects the mice from disease. Adoptive transfer of a Foxp3+cells from CII-tolerized mice confers a greater degree of protection when compared with transfer of equivalent numbers of Tregs from naïve mice.
Role of helper T cells in the loss of B cell anergy mediated by the absence of Tregs (115.6)
Authors: Gauld Stephen , De Santis Jessica , Hartog Nicholas , Josephson Jennifer , Leonardo Steven 
Published: January 2023

Abstract
Regulatory T cells (Tregs) are crucial for the maintenance of immune tolerance and the absence of Tregs results in significant autoantibody production. This suggests that Tregs play a key role in B cell tolerance. The mechanism by which Tregs regulate B cell tolerance has yet to be resolved but has important implications for our understanding of autoimmunity. Using both constitutive and inducible models, we show that the absence of Tregs results in autoantibody production, due to the loss of B cell anergy. Further studies show that this is dependent on the presence of helper T cells. We propose that the absence of Tregs results in the dysregulation of helper T cells that drive the loss of B cell anergy. Interestingly, our studies show the expansion of a CD4+GL7+ population in the absence of Tregs. Subsequent analysis shows that many of these cells express CXCR5 and thus resemble germinal-center TFH cells, an observation confirmed by their expression of Bcl6 and IL-21. We hypothesize that the absence of Tregs drives the expansion of TFH cells that play a role in the loss of B cell anergy. Characterization of this proposed mechanism may unveil new strategies for the treatment or prevention of autoantibody-mediated autoimmune diseases.
Aryl hydrocarbon receptor-mediated epigenetic modulation of Foxp3 and IL-17 genes results in differential regulation of regulatory T cells and Th17 cells and amelioration of experimental autoimmune encephalomyelitis (115.8)
Authors: Singh Narendra , Singh Udai , Rouse Michael , Nagarkatti Mitzi , Nagarkatti Prakash 
Published: January 2023

Abstract
AhR was earlier identified for its role in xenobiotic metabolism, recent studies have suggested that AhR may regulate T cell differentiation. To understand this further, we examined the effect of AhR activation on micro RNAs (miRNAs) profile in T cells, epigenetic modulation of Foxp3 and IL-17, and differentiation of Tregs and Th17 cells, using TCDD, an AhR ligand. Upon AhR activation, there was a significant difference in the miRNAs profiles in T cells. Analysis of some of these miRNAs showed their role in regulation of various genes, including Foxp3 and IL-17. Further examination of epigenetic effects of AhR activation on Foxp3 and IL-17 gene promoters, we observed significant demethylation of Foxp3 promoter but methylation of IL-17 promoter in the presence of TCDD. Also, culture of T cells in the presence of TCDD led to different degrees of T cell differentiation. There was a significant increase in Tregs but decrease in Th17 cells in the presence of TCDD. Using an EAE murine model of multiple sclerosis, we examined the effects of AhR activation on EAE symptoms. There was significant amelioration of EAE symptoms in mice treated with TCDD, compared to vehicle-treated mice. Also, there was significantly higher number of Tregs but lower number of Th17 cells in mice treated with TCDD. Together, these data demonstrated that AhR activation regulates epigenetic modulation and can have differential effects on T cell differentiation into Tregs/Th17 leading to immune suppression.