bluuebunny/crossref_metadata_2025_split huggingface dataset:
Examining the effect of a 10-week golf program on circulating markers of inflammation in healthy, older adults: a pilot study
Authors: Moore Jared , Kanwar Kiran , Salem George 
Published: February 2023

Abstract

Objective
Golf is a unique, multimodal recreational exercise that has been shown to provide physical and cognitive benefits to older adults; therefore, the purpose of this study was to investigate how golf also affects circulating inflammatory marker levels in healthy, older adults.

Methods
Fifteen older adults completed a 10-week golf program with blood draws before and after the program. Participants had blood drawn using EDTA collection tubes after a 10 hour overnight fast. Plasma was isolated and stored at −80°C for approximately 16 weeks until run using a Millipore human cytokine magnetic panel and hsCRP ELISA. Results are presented as percent change with mean±standard deviation. Hedge’s g effect sizes are also presented.

Results
12/15 participants completed pre and post blood draws. C-reactive protein (CRP) levels decreased by 49.80% (3.01±2.21 vs 1.51±1.50 mg/L; g = 0.73). Interferon gamma (IFNγ) decreased by 14.25% (11.28±7.04 vs 9.67±7.67 pg/mL; g = 0.20) and tumor necrosis factor alpha (TNFα) decreased by 10.64% (19.29±8.67 vs 17.24±8.15 pg/mL; g = 0.23). Interleukin-10 decreased by 5.51% (22.68±12.85 vs 21.43±10.91 pg/mL; g = 0.10).

Conclusions
This program was performed with healthy, older adults and demonstrated that a 10-week golf program is safe and feasible for this population, and likely influences markers of inflammation, particularly CRP. This pilot work may be used to inform future studies in older adults using recreational activities, such as golf, to examine not only fitness benefits but changes in levels of chronic inflammation.
The immunological profile of maternal obesity at 28 weeks gestation underpins common negative pregnancy outcomes
Authors: Rees April , Richards Oliver , Jones Nick , Thornton Catherine 
Published: February 2023

Abstract
Maternal obesity has been implicated in adverse pregnancy outcomes such as miscarriage, preeclampsia and gestational diabetes mellitus (GDM) and poses a risk to the neonate. There is a knowledge gap surrounding obesity and changes to the maternal immune system.
Hypothesis: Obesity exacerbates systemic inflammation in pregnant women at 28 weeks of gestation.
Samples: Peripheral blood was collected from fasted women at 26–28 weeks of gestation; all were GDM-negative

Results:
Insulin (p=&lt;0.0001) and PAI-1 (p=0.0487) levels were increased in obese versus non-obese pregnant women. Obese women had a relative neutrophilia (p=0.0429) accompanied by diminished eosinophil (p=0.0178) and NKT cell (p=0.0124) numbers. The inflammatory cytokine profile of MNCs was mostly unchanged with obesity but the Th profile of pregnant women with obesity appears skewed towards Th17: on stimulation with CytoStim™, IL-6 (p=0.0183), TNFα (p=0.0478), IL-17F (p=0.0183) and IL-22 (p=0.0183) levels were increased; Th2 cells (p=0.0250) were also reduced with maternal obesity. Monocyte phenotypes showed some changes with obesity; on intermediate monocytes, CD86 (p=0.0068) was decreased yet CD163 (p=0.0421) was increased, and CCR2 expression was elevated on classical (p=0.0040) and intermediate (p=0.0340) monocytes.
There is a shift to Th1 and Th17 in obesity in the general populations, whereas pregnancy is associated with a shift to Th2 and Treg. Here, we show that this profile is compromised in maternal obesity, which might underpin detrimental effects on pregnancy. Further research should investigate homogenous populations of cells such as eosinophils, monocytes and T cells, to further understand the immunological consequences of maternal obesity.
Absorption After Neural Tube Teratogenesis is Dependent on Maternal Immune Cell Function
Authors: Ott Katherine C , Oria Marc , Redden Catherine R , Kang Hee Kap , Skital Veronica , Turner Lucas E , Alhajjat Amir A , Duru Soner , Peiro Jose L , Shaaban Aimen F 
Published: February 2023

Abstract
Introduction: Neural tube defects (NTDs), are severe malformations of the developing central nervous system. After having a pregnancy affected by NTD, the recurrence risk increases 20x. The predisposition to having children affected by NTDs has not been explained and may relate to surveillance by the maternal immune system as maternal immune cells such as NK and T cells have been shown to traffic in the fetal circulation. We hypothesized that maternal NK and T cells are necessary for selective fetal absorption after the development of an NTD.

Methods:
We challenged this hypothesis in an outbred murine model of valproic acid (VA)-induced fetal neural tube teratogenesis (NTT) performed of pregnant CD1 dams at E8. To evaluate protection from NTTs, maternal NK cells were selectively eliminated (mAb PK136) on E7. Maternal CD4+ and CD8+ T cells were selectively eliminated (GK1.5 and 2.43) on E6. All litters were harvested on E14 and prevalence of NTT compared between each treatment group and untreated controls.

Results:
The frequency of litters with VA-induced NTT was significantly higher when maternal NK cells or maternal T cells were selectively depleted compared to controls (100% and 88.2% vs 80.0%, p&lt;0.05). Only 10% of NK depleted dams had greater than 3 late absorptions per litter and T cell depleted dams had 0% compared to controls that had 30%, p&lt;0.05. This data shows that both cell types play a critical role in the late absorption process. Litter sizes were similar between the groups.

Conclusion:
These findings demonstrate that selective fetal absorption for NTT is dependent on intact maternal immune cell function. Further studies are needed to define the roles that maternal NK and T cells have in the absorption process during abnormal development.
Immune cell composition at the feto-maternal interface in health and disease
Authors: Mihalic Zala Nikita , Raftopoulou Sofia Nikita , Santiso Ana Sanchez , Maitz Kathrin Stefanie , Kindler Oliver , Valadez-Cosmes Paulina , Heinemann Akos , Wadsack Christian , Kargl Julia 
Published: February 2023

Abstract

Objectives:
We hypothesize that innate and adaptive leukocyte infiltration, function and localization within the placenta is altered in health and disease and that immune cell interactions play a crucial role in maintaining immune tolerance at the fetal-maternal interface.

Methods:
To evaluate the complexity and differences of the immune landscape in decidua basalis we examine tissue samples from healthy women and women who developed gestational diabetes (GDM). We use flow cytometry (18-plex), fluorescent multiplex immunohistochemistry and gene expression analysis.

Results:
Preliminary data suggest abundant innate immune cell infiltration (macrophages and neutrophils) as well as accumulation of T-cell and NK cell subsets at the fetal-maternal interface. In gestational diabetes mellitus pregnancies, we were able to observe lower T cell infiltration when compared to healthy, which was not seen in obese pregnant women. However, in both groups (obese and GDM) there was a trend for lower T regulatory cell infiltration. For monocyte and macrophage populations a trend towards lower immune cell infiltration was observed in both obese and GDM pregnancies when compared to healthy. 70–80% of macrophages show M2 polarization, which suggest that they have an important role in anti-inflammatory processes during pregnancies. We could observe also abundant neutrophil infiltration (up to 20% of all leukocytes), although there was no difference between heathy and diseased pregnancies.

Conclusion:
Our study comprehends a detailed picture of the immune landscape at the fetal-maternal interface in normal and GMD pregnancies, which will aid our understanding of possible dysfunctional immune mechanisms.
Atlas of Human IL-6-induced Signaling in Peripheral Blood Mononuclear Cells in Health and Disease
Authors: Kothari Hema , McSkimming Chantel , Drago Fabrizio , Williams Corey M , Zunder Eli R , McNamara Coleen A 
Published: February 2023

Abstract

Objective:
IL-6 is implicated in the development of coronary artery disease (CAD), autoimmune (AI) disorders, and cytokine storm syndrome (CSS). IL-6 inhibitors are effective in treating AI disorders and are being tested for CAD and CSS. While some studies have reported on IL-6-induced STAT signaling in humans, a comprehensive map of IL-6 signaling in human immune cells is currently lacking. We developed a 32-antibody custom mass cytometry (CyTOF) panel to characterize IL-6 signaling across all major human immune cell subsets, and applied it to identify IL-6-induced immune signatures linked with unstable atherosclerotic plaque.

Methods:
Blood cells from healthy donors and CAD subjects undergoing virtual histology-intravascular ultrasound imaging were stimulated with IL-6, stained and ran in CyTOF. Unsupervised analytical tools (SPADE, UMAP, and Leiden clustering) were used to identify immune cell subsets and IL-6-induced intracellular phosphorylation status.

Results:
IL-6 induced STAT1 and STAT3 activation in CD4 and CD8 naïve T cell subsets and CD4 memory T subsets. Notably, we identified that IL-6 also activates STAT5 within the CD4 and CD8 naïve T subsets. IL-6 induced a much more robust activation of STAT1 as compared to STAT3 and STAT5. Other cell types such as CD14+ monocytes, and CD11c+ and CD123+ dendritic cells also showed IL-6-induced STAT activation. IL-6-induced phosphorylation of STAT1 and STAT3 in a novel PD-1+CD27−CD127lowCD4+ effector memory T cell subtype was associated with higher CAD burden and unstable plaque features.

Conclusions:
Findings are significant for mechanistic insights into IL-6-induced inflammation and may enable discovery of new approaches to reduce inflammation in CAD and other pathologies.
A Novel approach towards Drug Design
Authors: Sika-Paotonu Dianne 
Published: February 2023

Abstract
Acute Rheumatic Fever (ARF) is the body’s autoimmune reaction to an untreated Group A Streptococcal (GAS) throat or skin infection. When recurrent and/or severe ARF episodes occur and are left untreated, this can trigger a condition known as Rheumatic Heart Disease (RHD) - permanent cardiac damage that can result and a major cause of morbidity and mortality worldwide. Without a GAS vaccine, painful monthly injections of Benzathine Penicillin G (BPG) are given intramuscularly to prevent GAS infections that may lead to further ARF episodes and trigger RHD if untreated. These injections are known as secondary prophylaxis and are given for at least 10 years, or sometimes a lifetime. In Aotearoa/New Zealand and the Pacific Region, Indigenous Māori and Pacific children and young people remain disproportionately affected by ARF and RHD. Work is currently underway towards a new Penicillin for ARF/RHD prevention which is more appropriate for children and young people who require these injections. Ideally, a longer lasting Penicillin that is less painful to be given is needed. The purpose of this work was to incorporate the Kakala Indigenous Pacific framework within research efforts involving Indigenous Māori and Pacific communities impacted by ARF and RHD. Application of the Indigenous Kakala research framework supported inclusivity, respect, reciprocity and ensured a strong focus on fostering respectful relationships between researchers and vulnerable communities, appropriate to cultural contexts for Pacific Peoples in Aotearoa/New Zealand. This highlights the importance of Indigenous frameworks and their application within Immunology based research work efforts to improve engagement and applicability within cultural settings.
TIM-3 drives temporal differences in restimulation-induced cell death sensitivity in effector CD8+ T cells in conjunction with CEACAM1
Authors: Lake Camille , Voss Kelsey , Bauman Bradly M. , Pohida Katherine , Jiang Timothy , Dveksler Gabriela , Snow Andrew L. 
Published: February 2023

Abstract
Immune homeostasis depends upon effective clearance of pathogens while simultaneously preventing immunopathology in the host. Restimulation-induced cell death (RICD) is one such mechanism where by activated T cells receive subsequent antigenic stimulation, reach a critical signal threshold through the T cell receptor (TCR), and commit to apoptosis. Many details of this process remain unclear, including the role of proteins that influence the TCR signaling cascade. Here we characterize the role of T cell immunoglobulin and mucin domain containing 3 (TIM-3) in RICD regulation. TIM-3 protected newly activated CD8+ effector T cells from premature RICD during clonal expansion. Surprisingly, however, we found that TIM-3 potentiated RICD in late-stage effector T cells. The presence of TIM-3 increased proximal TCR signaling and pro-apoptotic protein expression in late-stage effector T cells, with no consistent signaling effects in newly activated cells. We found that TIM-3 was expressed on the surface of newly activated effector T cells, but remained largely intracellular in late-stage effector cells. Consistent with this, TIM-3 required a ligand to prevent early RICD only immediately after activation. We found that CEACAM1, a known ligand of TIM-3, protected newly activated cells from premature RICD, with no measurable effects in late-stage effectors. Indeed, CEACAM1 enabled TIM-3 surface expression on T cells, implying a co-dependency for these proteins in protecting expanding T cells from premature RICD. Our findings suggest that co-signaling proteins like TIM-3 and CEACAM1 can alter RICD sensitivity at different stages of the effector T cell response, with important implications for checkpoint blockade therapy.
Tumor Necrosis Factor Alpha inhibits humoral immunity by regulating the antibody secreting cell bone marrow niche
Authors: Aaron Tonya , Fooksman David R 
Published: February 2023

Abstract
Humoral immunity is a critical component of the immune memory, and its longevity is partly dependent on the survival of antibody-secreting cells (ASC). Previous studies have shown that several types of infections can deplete pre-existing antibody titers, but the exact mechanism of this process is unclear. Most, if not all, forms of infection induce inflammation including Tumor Necrosis Factor Alpha (TNFa). Here we show that TNFa-mediated inflammation depletes pre-existing antibody titers by limiting ASC retention in the bone marrow (BM) survival niche. Acute recombinant TNFa (rTNFa) treatment induces ASC egress from the BM into the blood and limits engraftment of adoptively transferred ASCs into the BM of recipient mice. To determine if the TNFa-mediated ASC egress from the BM was cell-intrinsic or –extrinsic, we generated BM chimeras with wild-type and TNFa receptor knockout mice. We found that TNFa signaling through TNFa receptor 1 in non-hematopoietic cells induces ASC egress from the BM in a cell-extrinsic manner. Treatment with rTNFa did not induce ASC death in the BM, but it increased glucose uptake and expression of CXCR4, a receptor involved in ASC retention in the BM. In contrast, mobilized ASCs in the blood had reduced glucose uptake, CD98 expression, and CD93 expression suggesting that ASC metabolism is highly dependent on the BM niche. Our findings demonstrate that inflammation alters ASC physiology in both cell-intrinsic and extrinsic manners, leading to reduced antibody titers and long-term immune memory.
Treg-expressed CTLA-4 depletes CD80/CD86 by trogocytosis, releasing free PD-L1 on antigen-presenting cells
Authors: TEKGUC MURAT , WING JAMES BADGER , OSAKI MOTONAO , LONG JIA , SAKAGUCHI SHIMON 
Published: February 2023

Abstract
Foxp3-expressing CD4+CD25+ regulatory T cells (Tregs) are engaged in the maintenance of immunological self-tolerance and homeostasis. They constitutively and highly express the immune checkpoint receptor CTLA-4, whose Treg-specific deficiency causes severe systemic autoimmunity. As a key mechanism of Treg-mediated suppression, CTLA-4 downregulates the expression of CD80/CD86 costimulatory ligands on antigen-presenting cells (APCs). Here we showed that CTLA-4 facilitated the immune synapse formation and conjugation of Tregs and APCs. These conjugates thus provided stable platforms whereby Tregs were able to deplete CD80/CD86 proteins on APCs by uptaking them via CTLA-4-dependent trogocytosis. The depletion occurred even with Tregs expressing a mutant CTLA-4 lacking the cytoplasmic portion required for its endocytosis. The CTLA-4-dependent trogocytosis of CD80/CD86 also accelerated in vitro and in vivo passive transfer of other membrane proteins and lipid molecules from APCs to Tregs without their significant reduction on the APC surface. Furthermore, CD80 downregulation or blockade by the Treg-expressed membrane CTLA-4 or its solubilized form, respectively, disrupted cis-CD80/PD-L1 heterodimers and increased free PD-L1 on dendritic cells. Taken together, Tregs can exert dual suppressive effects on T-cell immune responses by converting highly stimulatory (CD80highfree PD-L1low) DCs to non-stimulatory/inhibitory (CD80lowfree PD-L1high) DCs via CTLA-4-dependent trogocytosis. Immune checkpoint blockade therapies with the combination of anti-CTLA-4 and anti-PD-1/PD-L1 antibodies may therefore synergistically hinder Treg-mediated immune suppression, thereby effectively enhancing tumor immunity.
Regulatory T cells suppress antigen-specific CD8+ T cells in vivo by modulating the immune-synapse
Authors: Mansoori Mohammad Nizam , Kamenyeva Olena , Kabat Juraj , Shevach Ethan M 
Published: February 2023

Abstract
T Regulatory cells (Tregs) plays an important role in regulating self and foreign antigens related immune response by different mechanisms. Recent studies have shown that antigen-specific Treg suppress CD4+ effectors T cells in vitro and in vivo by depleting peptide-MHC-II complexes from the DC surface. These, results raise questions as to how Treg suppress CD8+ T effectors, particularly in vivo. To explore Treg mediated suppression of CD8+ T cells, we generated CD4+ iTregs from OT-II mice specific for Ova323–339 in association with I-Ab and determined their capacity to suppress CD8+ T cells from OT-I mice specific for Ova257–264 (SIINFEKL) in association with H-2Kb. CD4+ OT-II iTreg suppressed the in vitro proliferation of OT-I T cells in the presence of dendritic cells (DCs) pulsed with both Ova323–339 and Ova257–264 or with DCs singly pulsed with each peptide. Surprisingly, the expansion of OT-I CD8+ T cells in vivo was not suppressed by OT-II iTreg when the two peptides were presented on separately pulsed DCs, but was suppressed when both peptides were presented on the same DCs. OT-II Tregs depleted the Kb-SIINFEKL complex from the DC surface by a process of trogocytosis in vitro only in presence of their cognate antigen. Imaging experiments in vivo depict a close interaction between Tregs and CD8+ T cells suggesting that suppression of CD8+ T cells in vivo requires close proximity between Treg and responder CD8+ T cell and that pMHCI and pMHCII complexes may be closely associated in the immune synapse.
Dynamic Adoption of Anergy by Antigen-Exhausted CD4+ T Cells
Authors: Kadam Pallavi , Trefzer Anne , Wang Shu-Hung , Pennavaria Stefanie , Lober Benedikt , Akcabozan Batuhan , Kranich Jan , Brocker Thomas , Nakano Naoko , Irmler Martin , Beckers Johannes , Straub Tobias , Obst Reinhard 
Published: February 2023

Abstract
Exhausted immune responses to chronic diseases represent a major challenge to global health. To explore their cell fate and plasticity in exhaustion, we analyzed CD4+T cells in a mouse model with regulatable antigen presentation. When the cells are driven through the effector phase, and are then exposed to different levels of persistent antigen, they lose their Th1 functions, upregulate exhaustion markers, resemble naturally anergic cells and become unable to help B cells and, at the highest dose, undergo apoptosis. Mechanistically, TCR signaling pathways are modulated with increasing dose and time. Ca2+ fluxes were found to be more robust to persistent antigen presentation while the MAPK and Akt pathways are easily desensitized. Transcriptomic analyses show the dynamic adjustment of gene expression and the accumulation of TCR signals over a period of weeks. Upon antigen removal, the cells recover their functionality while losing exhaustion and anergy markers. Preliminary data indicate that antigen-exhausted CD4+T cells retain their plasticity for at least 30 days and are able to adjust to different levels of antigen. Our data suggest a dynamic response of CD4+ T cells to different levels of persisting antigen and contribute to a better understanding of chronic disease.
Prenatally Educated Friendly NK Cells Suppress Allospecific T cell Responses and Expand Foxp3+CD4+Treg Cells.
Authors: Kang Hee Kap , Otto Katherine C , Turner Lucas E , Redden Catherine R , Skital Veronica M , Alhajjat Amir A , Scorletti Federico , Shaaban Aimen F 
Published: February 2023

Abstract
Prenatal allospecific tolerance hinges on the developmental selection of NK cells expressing a “friendly” phenotype that is not cytotoxic to allogeneic donor cells. Prenatally educated friendly NK cells (fNK’s) that express a tolerant alloreceptor phenotype toward the donor cells also exert suppressive effects on T cell alloimmunity in vivo and in vitro through direct cell contact. Little is known about the mechanisms regulating this suppression. Therefore, we hypothesized that fNK’s suppress induction of allospecific T cell responses through TGF-beta expression.
To challenge this hypothesis, fNK cells were stimulated with PMA/Ionomycin (1ug/ml each) for 6h and supplemented with brefeldin A for the final 4 hours. TGF (LAP) was detected by intracellular flow cytometry. Following stimulation fNK’s from engrafter mice expressed significantly higher levels of TGF-beta when compared to fNK’s from naïve mice. Furthermore, when naïve splenocytes and allogeneic targets were co-cultured with fNK’s from engrafter mice, an expansion in the frequency of regulatory T cells was noted. Conversely, no change in Treg frequency was seen when co-cultured with fNK’s from naïve mice.
From these results, we conclude that prenatally educated friendly NK cell exert antigen-specific suppressive effects on T cell immunity through TGF-b expression and Treg expansion.
Epigenetic and transcriptional programs of CD4+ T cell anergy
Authors: Titcombe Philip J , Morales Milagros Silva , Mueller Daniel L 
Published: February 2023

Abstract
T cell tolerance is critical to avoid autoimmunity and resolve inflammation. CD4+ T cells that recognize self-antigens in the periphery can exert active suppression as regulatory T cells (Treg) or enter an inactive state known as anergy. Recent evidence suggests that anergy occurs naturally within a subpopulation of polyclonal CD4+ T cells and can generate precursors to Foxp3-expressing Treg cells. We aimed to identify transcription factors underlying T cell anergy induction and its potential plasticity. Polyclonal anergic CD4+ T cells from untreated wildtype mice were sorted based on previously reported markers and compared to naïve, effector-memory, and Treg cell populations identified within the same samples. Paired epigenome and transcriptome analysis revealed a unique anergy signature driven by bZIP family (Batf, Nfil3), NFAT family (Nfatc1), and EGR family (Egr3, Egr4) transcription factors. Following tolerization by repeated peptide infusions, antigen-specific CD4+ T cells from Batf-deficient mice demonstrated exaggerated expansion and minimal Foxp3+ Treg cell differentiation. Our data suggest that a unique transcription factor network, including BATF, generates and maintains peripheral CD4+ T cell anergy.