bluuebunny/crossref_metadata_2025_split huggingface dataset:
Aging-associated alterations in lymphatic vessels and mast cells in perilymphatic tissues
Authors: Pal Sarit , Meininger Cynthia J. , Gasheva Olga , Griffith William , Zawieja David C. , Gashev Anatoliy A. 
Published: January 2023

Abstract
Aging alters lymphatic vessel structure (by increasing the size of low muscle cell investiture zones), ultrastructure (through loss of the glycocalyx), and proteome composition causing a concomitant increase in lymphatic permeability. Our recent studies have shown that the contractile function of aged lymphatic vessels is depleted with abolished role of nitric oxide and an increased role of lymphatic-born histamine in flow-dependent regulation of lymphatic phasic contractions and tone. Thus, aging-related reduced vessel functionality and increased oxidative stress of the lymphatic vasculature facilitate the spread of pathogens into perilymphatic tissues. In addition, aging causes the basal activation of the perilymphatic mast cells, which, in turn, restricts the recruitment/activation of MHCII+ -positive cells and eosinophils in perilymphatic tissues. This aging-associated basal activation of perilymphatic mast cells limits proper functioning of the mast cell/histamine/NF-kB axis that is essential for the regulation of lymphatic vessel transport and barrier functions as well as for both the interaction and trafficking of immune cells near and within lymphatic collecting vessels. Cumulatively these alterations play crucial roles in the progression of aging-related pathogenesis in inflammation and immunity.
The role of Runx1 in the regulation of T cell tolerance
Authors: Wilfahrt Drew Nicholas , Hsu Fan-Chi , Chung Julia , Arocha Sinibaldo Romero , Schwab Aaron , Shapiro Virginia Smith 
Published: January 2023

Abstract
The transcription factor Runx1 is critical for T cell development and maturation. CD4-Cre Runx1 conditional knockout mice have a block in T cell maturation, leading to complement deposition on CD4+ recent thymic emigrants, leaving very few CD4+ T cells in peripheral lymphoid organs. Consistent with a block in maturation, peripheral Runx1-deficient CD4+ T cells fail to produce normal levels of TNF-a upon stimulation. These CD4+ T cells that persist in CD4-Cre Runx1 cKO mice possess a phenotype not found in other genetically modified mice with a block in T cell maturation. Thymic- and splenic-derived T cells from the CD4-Cre Runx1 cKO exhibit altered expression of markers indicative of anergy including FR4 and CD73. This suggests Runx1 plays a role in regulating the development of T cell tolerance which is disrupted upon deletion of Runx1 in CD4+ T Cells. To test this, we have generated a mixed bone marrow chimera (BMC) system with Estrogen Receptor-Cre Runx1 knockout and B6.SJL bone marrow to knock out Runx1 in mature T cells. Surprisingly, in the mixed BMC both the ER-Cre Runx1 cKO and the B6.SJL peripheral T cells acquire a functionally hyporesponsive phenotype, suggesting that Runx1 regulates an extrinsic signaling mechanism controlling tolerance. Moving forward, this BMC model allows us to investigate the development of this anergic phenotype in mature T cells, and tests the hypothesis that Runx1 plays a critical role in regulating T cell tolerance.
Mechanism underlying the induction of Foxp3+ regulatory T cells by lactoferrin
Authors: Kim Pyeung-Hyeun , Jang Young-Saeng , Song Ha-Eon , Seo Goo-Young , Kang Seung-Goo , Lee Jeong Hyun , Kwon Bo-Eun , Ko Hyun-Jeong 
Published: January 2023

Abstract
Lactoferrin (LF) is multifunctional in the immune response. We have previously demonstrated that LF acts like TGF-β in IgA B cell differentiation. Therein, we explored whether LF affects peripheral regulatory T cell (Treg) differentiation. Indeed, LF induced Foxp3+ Treg differentiation by itself and in combination with TGF-β1 synergized to express Foxp3. It was conceivable that LF may increase Foxp3 expression through secretion of active TGF-β or facilitating latent TGF-β to active form. There was little active TGF-β in the supernatant from LF-stimulated T cells. Surprisingly, however, pan anti-TGFβ Ab completely abolished the LF-induced Foxp3 expression, suggesting that membrane-bound TGF-β may be involved. In this, we found that both LF and TGF-β1 increase latency-associated peptide negative (LAP−)TGF-β on the surface of Foxp3+T cells, and this increase was more dramatic when treated with LF plus TGF-β1. As was the case in B cells, LF-induced Foxp3 expression was virtually disappeared by pretreatment with soluble TβRIII. Collectively, these results suggest that LF induces Foxp3+Treg through TβRIII and subsequent expression of membrane-bound/LAP-negative TGF-β.
Prostaglandin I2 promotes Treg function in vitro
Authors: Norlander Allison Elizabeth , Bloodworth Melissa H. , Peebles R. Stokes 
Published: January 2023

Abstract
Our laboratory has shown in recent years that prostaglandin I2 (PGI2) promotes immune tolerance through inhibition of T cell and dendritic cell function. Specifically, we have shown that PGI2 is able to restrain Th1 and Th2 immune responses, suggesting that it has immunosuppressive properties. However, PGI2’s impact on the functionality of T regulatory (Treg) cells, a T cell subtype important for the suppression/resolution of immune responses which express the canonical transcription factor forkhead box p3 (Foxp3), is unknown. Thus, we hypothesized that PGI2 promotes the function of Tregs. To test this hypothesis, we utilized mice deficient in IP (IP KO), the receptor for PGI2.. We found that splenic Tregs from IP KO mice have a significantly lower mean fluorescence intensity (MFI) of Foxp3 compared to wild-type (WT) Tregs. Furthermore, the percent suppression of CFSE-stained WT effector T cells by IP KO Tregs was significantly decreased compared to the percent suppression of CFSE-stained WT effector T cells by WT Tregs. Moreover, the percentage of induced Tregs (iTregs) generated from naïve T cells isolated from IP KO mice was significantly reduced compared to WT mice. As a whole, our preliminary data demonstrate the ability of PGI2 to promote Treg function, and thus suggest that PGI2 may serve as a novel treatment strategy for T cell mediated diseases.
The generation of memory CD8 T cells is regulated by intracellular Galectin-3
Authors: Farhad Mohammad , Redmond William L. 
Published: January 2023

Abstract
The ability of tumors to induce immunosuppression and reduce the cytolytic function of tumor-infiltrating lymphocytes (TIL) is a major obstacle to creating effective therapies for cancer patients. The levels of Galectin-3 (Gal3) protein are increased during tumor progression in many cancers. Gal3 induces the polarization of tumor-associated macrophages and plays a role in the survival and metastasis of cancer cells. Gal3 is functional within cells as well as in the extracellular space and recent studies suggest that it has opposing functions in these two compartments. The biology of extracellular Gal3 has been extensively studied, however, the function and mechanisms by which intracellular Gal3 regulates CD8 T cells responses are poorly understood. CD8+ T cells are a critical component of anti-tumor immunity and enhancing their function can promote tumor elimination. Intracellular Gal3 has been suggested to positively regulate CD8+ T cell activation and survival. In the current study, we demonstrate that Gal3-deficient CD8+ T cells has no defect in early activation in vitro. However, Gal3−/− OT-I CD8+ T cells exhibit decreased proliferation, activation, survival and transition to memory in response to cognate antigen in vivo. Together, these data implicate Gal3 as a critical mediator of CD8 T cell survival and memory formation following antigen challenge in vivo.
PSGL-1 regulates the extent of TCR-dependent activation in T cells and prevents their suppression by Tregs
Authors: Otero Dennis C. , Takahashi Amy , Chao Grace , Leung Donmienne , Bradley Linda 
Published: January 2023

Abstract
We recently demonstrated that PSGL-1 (P-selectin glycoprotein-1) could act as a T cell-intrinsic checkpoint inhibitor during chronic viral infection. As such, PSGL-1 may be a viable target to control T cell responses in the setting of autoimmune disease. In this study, we investigated the role of PSGL-1 on the activation of T cells and in mouse models of autoimmune disease. Here we find that the lack of PSGL-1 on T cells results in clinically worse disease in both EAE and adoptive transfer colitis, which supports its function as a negative regulator of T cell activation. However, in vivo treatment with an anti-PSGL-1 antibody known to block binding of the ligand, P-selectin, from the time of disease initiation had little effect on disease severity in the transfer colitis model and led to exacerbated disease in the EAE model. Crosslinking PSGL-1 on naïve T cells in vitro in the presence of TCR signals results in up-regulation of PD-1 but also up-regulation of other activation markers, suggesting that PSGL-1 exerts regulatory effects during the early activation program in T cells. Surprisingly, however, in an in vitro assay, crosslinking PSGL-1 on effector T cells resulted in resistance to regulatory T cell suppression. Therefore, anti-PSGL-1 treatment results in enhanced T cell activation and resistance to Treg suppression, thereby leading to more severe autoimmune disease by altering/blocking PSGL-1 signaling to phenocopy PSGL-1-deficiency.
A mechanism involving sibling transcription factor assistance preserves the integrity of an active Foxp3 locus in peripherally induced regulatory T cells.
Authors: Ghosh Sayantani , Rubtsov Yuri P. , Jung Haejin , Roy-Chowdhuri Sinchita , kang Keunso , Im Sin-hyeog , Surh Charles D. , Rudensky Alexander Y. , Rudra Dipayan 
Published: January 2023

Abstract
Regulatory T (Treg) cell mediated dominant negative regulation is critical for suppressing hyper-immune responses. Broadly classified as thymus derived (tTreg) and peripherally induced (iTreg), these cells share a stringent dependence on the transcription factor Foxp3. In spite of significant advances, precise understanding of the molecular events that promote and preserve unceasing expression of Foxp3 in Treg cells is still incompletely understood. Here we show that Foxp1, a forkhead transcription factor and thus a sibling family member of Foxp3, is essential for sustained high level expression of Foxp3 specifically in iTreg cells. By being readily associated with the Foxp3 locus in a TGFβ dependent manner, Foxp1 critically participates during multiple phases of iTreg development and maturity. By employing an inducible model of temporal deletion of Foxp1 in precursor CD4+ T cells, we found that it is required for optimum expression of Foxp3 during the onset of iTreg induction. Even a conditional ablation of Foxp1 in iTreg cells at a later developmental time point, when high level transcription of Foxp3 was already established, resulted in dramatic instability of the differentiated cell state. Accordingly, Treg specific deletion of Foxp1 renders cells gradually lose Foxp3, resulting in dramatically reduced Nrp1−Helios− iTreg compartment in mice, ensuing significantly augmented intestinal inflammation. Interestingly, the stability of Foxp3 expression in tTreg cells remained unaffected in the absence of Foxp1. Thus, our study unravels a mechanistic module of evolutionarily akin members of a transcription factor subfamily in establishing a novel molecular program indispensable to ensure efficient immune homeostasis.
VSIG-8 is a co-inhibitory ligand and an immune checkpoint molecule for human T cells
Authors: Wang Jinghua , Manick Brian , Renelt Mark , Hansen Louis , Wu Guoping , Kalabokis Vassilios 
Published: January 2023

Abstract
Cell surface-localized and secreted immunoglobulin superfamily (IgSF) proteins play central roles in regulating adaptive and innate immune responses, and are primary targets for the development of new immunotherapeutics. In this work we provide biologic-functional insight for VISG-8, one member of this important class of proteins. VSIG-8 inhibits the production of cytokines (IL-2, IFN-gamma, IL-17, IL-6, and IL-19), chemokines (MCP-1, MCP-10, and IP-10) and other proteins (IGFBP3 and RBP4) on anti-CD3 activated human CD3 T cells. Furthermore, VSIG-8 significantly reduces the production of IFN-gamma and IL-2 on both CD4 and CD8 T cells in the presence of T-cell receptor signaling. In addition, VSIG-8 markedly suppresses anti-CD3-induced human T cell proliferation. Moreover, VSIG-8 profoundly decreases the conversion of naïve CD4+ T cells into Th1 cells. Thus, we have identified VSIG-8 as a new immune checkpoint molecule that is able to inhibit human T-cell activation. This novel human T-cell co-inhibitory ligand may be a unique target for developing new immunotherapy strategies for the treatment of human cancers, autoimmune disorders, and infection diseases.
Id protein function in adipose resident regulatory T cells
Authors: Frias Adolfo B. , Ji Junyi , Buechel Heather Marie , Hand Timothy , D’Cruz Louise M. 
Published: January 2023

Abstract
Immune cells in the visceral adipose tissue play critical roles in modulating chronic system inflammation associated with obesity and type II diabetes. Studies have shown that CD4+ FoxP3+ adipose resident regulatory T cells (aTregs) restrict inflammation through their anti-inflammatory properties, such as production of high levels of IL-10. This population of aTregs is severely decreased in mice fed a high-fat-diet (HFD), indicating a critical role for these cells in regulating obesity-associated inflammation. However, the transcriptional programs that sustain the differentiation and survival of these cells are poorly understood. Using reporter mice, we show that Id2, a negative regulator of the E protein transcription factors, is highly expressed in aTregs while lymphoid Tregs have an inverse expression profile with low Id2 and high Id3 expression. Our preliminary data using Id2 and Id3 Treg specific conditional deficient mice show that Id2 deficiency results in a severe reduction in aTregs. Moreover, Id2-deficient aTregs displayed low expression of key aTreg markers such as ST-2, KLRG1, and CCR2. Loss of Id3, in contrast, resulted in increased aTreg frequency, suggesting the reciprocal expression of these two transcriptional regulators is essential for maintaining the aTreg transcriptional program. We postulate that Id2 is required by aTregs to support aTreg survival and function. Understanding the transcriptional regulation of aTregs will allow for better understanding and treatment of chronic inflammation associated with obesity and type II diabetes.
Stem cell-like T-bet+ IgM memory cells generate multi-lineage effector B cells
Authors: Levack Russell C. , Kenderes Kevin J. , Cabrera-Martinez Berenice , Winslow Gary 
Published: January 2023

Abstract
Our laboratory has been studying the differentiation of CD11c+ T-bet+ IgM memory B cells during secondary ehrlichial infection.
These cells are closely related to B cells that have been described in a range of other contexts, including hepatitis, AIDs, malaria, SLE, and age-related autoimmunity.
Following secondary infection, IgM memory cells, as a population, undergo self-renewal, and differentiate into effector cells, including splenic and bone marrow antibody secreting cells (ASC).
Moreover, IgM memory cells enter germinal centers, where they undergo class-switch recombination and give rise to class-switched memory and effector cells.
Although these data suggest that a single memory cell has multi-lineage potential, we sought to formally address this question by searching for shared clones among IgM memory cell-derived effector cells.
Among the IgM memory cell-derived subsets, we identified several clones common to all effector cell populations. The number of common clones varied for each pairwise comparison of effector cells and suggested lineal relationships.
IgM memory cells accumulated mutations following rechallenge; although all memory cell-derived subsets displayed similar numbers of V region mutations.
Lineage analysis demonstrated that the effector cell subsets underwent varying degrees of clonal diversification, although this was clone-dependent.
These studies reveal that a single IgM memory cell clone can give rise to different memory and effector cell subsets, that is, they exhibit stem cell properties. This property distinguishes these T-bet+ IgM memory cells as a unique memory cell subset.
T Follicular Regulatory (TFR) Cells Regulate B Cell Responses in Both, T-cell Dependent and Independent Pathways
Authors: Lopez-Ocasio Maria D. 
Published: January 2023

Abstract
Production of high-affinity antibody-secreting plasma cells and memory B cells requires interaction of TFH cells with B cells in the follicle. TFR cells, a subset of Foxp3+ Tregs, localize into follicles, regulating GC responses. To elucidate the mechanisms and cellular targets used by TFR cells to suppress GC responses, we quantitated their function in vitro. In the absence of TFR cells, TFH from primed mice induce naive B cell differentiation into GC B cells and class switching in the presence of anti-CD3 alone or anti-IgM/anti-CD3 in a contact dependent manner. Addition of TFR cells from primed mice efficiently suppressed GC B cell differentiation and class switching in the anti-CD3 alone cultures, but moderately suppressed BCR-stimulated B cells. Under anti-CD3 conditions, IL-4−/− TFH cells did not promote B cell differentiation and class switching. In contrast, IL-21R−/− B cells differentiated into GC B cells with a reduced number of IgG1+ cells. When IL-4−/− TFH cells were co-cultured with IL-21R−/− B cells, both GC differentiation and class switching were reduced. Under anti-IgM/anti-CD3 conditions, IL-4−/− TFH cells promoted B cell differentiation, but class switching was reduced, while IL-21R−/− B cells differentiated normally into GC B cells, with reduced class switching. When B cells alone were stimulated in culture with either LPS or CpG, TFR cells did not block B cell proliferation, but their differentiation into plasma cells was reduced. These studies suggest that in vitro, TFR cells regulate GC responses primarily by acting on TFH cells by inhibiting cytokine production and CD40L expression, but can also directly suppress some aspects of B cell differentiation.
Supported by the Intramural Research Program of the NIAID.
Preoperative exercise therapy protects the liver from ischemia-reperfusion injury
Authors: Zhang Hongji , Ren Jinghua , Yazdani Hamza O. , Van Der Windt Dirk , Zhang Jinxiang , Tsung Allan , Huang Hai 
Published: January 2023

Abstract

Introduction
Surgical stress such as hepatic ischemia/reperfusion (I/R) injury results in an increased risk of postoperative morbidity and mortality, including liver transplantation. Preoperative exercise therapy has been shown to enhance physical capacity at the moment of hospital admission and may facilitate better recovery after surgery. However, the mechanisms behind this protection remain to be elucidated. Here we hypothesize that preoperative aerobic exercise therapy has protective effects as a result of inhibiting sterile inflammatory processes after liver I/R injury.

Methods
Eight-week-old male C57BL/6 mice were randomly divided into exercise (n=15) or sedentary (n=15) groups. The exercise group ran on a motorized treadmill for 60 min/day, 5 days/week at a speed of 12.5m/min for 4 weeks. 70% partial liver warm I/R was performed in both groups of mice at 72 hours after the final exercise session.

Results
After 4 weeks,60% exercised mice showed a 3%–6% weight loss whereas the weight of all sedentary mice were increased. The sALT levels was significantly reduced in the exercise mice than the sedentary mice after liver I/R. Significantly increased Natural Killer (NK) cells were observed, whereas less neutrophil infiltration was seen in exercise mice after I/R, suggesting a link between hepatic immune modulation and exercise. Moreover, the lactate dehydrogenase (LDH), apoptosis, reactive oxygen species (ROS) in hepatocyte were all decreased in exercise mice.

Conclusions
These data show beneficial effects of preoperative exercise therapy on the experimental model of liver I/R injury, which offer a rationale for encouraging predisposed patients of HCC or other end-stage liver diseases that need liver surgery.
The transcription factor ROR alpha preserves group 3 innate lymphoid cell lineage identity and function
Authors: Messing Melina , Lo Bernard C. , Hughes Michael R. , Hernaez Diana Canals , McNagny Kelly M. 
Published: January 2023

Abstract
Innate lymphoid cells (ILCs) are critical for host defense and tissue repair. The transcription factor RORα is essential for ILC2 development but it is also highly expressed by ILC3s where its function remains poorly defined. Previously, we found that Rorasg/sg bone marrow transplant (BMT) mice were protected from intestinal fibrosis in a Salmonella--induced model of Crohn’s disease and that this is due to defective cytokine production by ILC3s. In the current study, whole transcriptome sequencing analysis reveals a striking downregulation of ILC3 signature genes in RORα-deficient ILC3s isolated from Salmonella infected mice. In particular, the expression of genes involved in sensing an inflammatory milieu is attenuated. Moreover, we find that Rorasg/sg ILC3s fail to express IL-17A following ex vivo stimulation with IL-23 and IL-1β. Consistent with these observations, we also find that Rorasg/sg BMT mice are more susceptible to Citrobacter rodentium infection due to attenuated expression of IL-22 and impaired induction of antimicrobial peptides. Collectively, our data suggests that RORα plays a key role in preserving functional ILC3s by modulating their ability to sense environmental cues that stimulate the efficient production of cytokines. These observations also suggest that targeting ILC3 cells could be of therapeutic benefit in fibrosis associated with Crohn’s disease.
Modulation of oxidative burst with exposure to cytokines in neutrophil cell activation
Authors: Swain Pamela , Romero Natalia , Dranka Brian P. 
Published: January 2023

Abstract
Neutrophils are essential for killing microorganisms and have a significant role in regulation of inflammatory response. Generation of reactive oxygen species (ROS) is one of the critical events that modulate the immune response in phagocytic cells. Stimulated neutrophils activate membrane-associated NADPH oxidase (NOX2) resulting in a powerful oxidative burst during which a large amount of oxygen is consumed generating ROS. The Agilent Seahorse XF analyzer is used to quantify oxygen consumption rate (OCR) as a direct non-invasive measure of neutrophil activation. In this study, neutrophil activation in the presence of cytokines known to be expressed within microenvironments in normal and disease states is evaluated. Treatment of neutrophils with the inflammatory cytokine TNFα induces oxidative burst within an hour of treatment, as observed in real time using the XF analyzer. Interestingly, pretreatment with TNFα reduces the oxidative burst observed when neutrophils were activated with phorbol myristate acetate (PMA). In contrast, treatment with GM-CSF and IL1 β had no acute effect in inducing oxidative burst. Rather, pretreatment of neutrophils with GM-CSF and IL1 β primed them for an enhanced response to PMA and a reduced elapsed time to reach maximal activation. Of note, the oxidative burst observed is associated with simultaneous increased of proton efflux rate (PER), indicative of the dependence on glycolysis and pentose phosphate pathway for production of NADPH during oxidative burst. These results, show the utility of the XF neutrophil activation assay to study the effect of modulators such drug treatments, microenvironment and disease progression during innate immune response.