bluuebunny/crossref_metadata_2025_split huggingface dataset:
Deficiency of epidermal fatty acid-binding protein promotes Foxp3 expression in adaptive T regulatory cells (113.22)
Authors: Li Bing , Zhang Lihua , Hansen Richard , Stout Robert , Suttles Jill 
Published: January 2023

Abstract
Fatty acid-binding proteins (FABPs) are cytosolic proteins that serve as intracellular lipid chaperones. In previous work we demonstrated that CD4+ T cells deficient for expression of epidermal fatty acid-binding protein (E-FABP) exhibit elevated activity of peroxisome proliferator-activating receptor γ (PPARγ) which suppressed IL-6-induced STAT3 activity, resulting in suppression of Th17 differentiation. E-FABP-deficiency was accompanied by enhanced levels of FoxP3+ CD4+ T cells in vivo. Herein, we demonstrate that E-FABP deficiency promotes TGF-β-induced Foxp3 expression in adaptive T regulatory cells. These cells are characterized by enhanced PPARγ and AMP-activated protein kinase (AMPK) activities with elevated TGF-β and IL-10 production, but normal Smad2 and Smad3 phosphorylation. AMPK activators, but not PPARγ agonists, increased TGF-β-driven Foxp3 expression, yet inhibition of either AMPK or PPARγ downregulated Foxp3 expression. AMPKα1 deficiency results in impaired Foxp3 induction upon TGF-β stimulation. Taken together, our data reveal that E-FABP deficiency in CD4+ T cells enhances Foxp3 expression via PPARγ-AMPK-mediated pathway(s).
miRNA regulates the Glycoprotein A repetitions predominant expression in Tregs (113.23)
Authors: Zhou Qihui , Schnabel Christine , Schulze-Koops Hendrik , Skapenko Alla 
Published: January 2023

Abstract
Regulatory T cells (Tregs) are important for maintaining peripheral tolerance. A novel surface protein, Glycoprotein A repetitions predominant (GARP) was recently identified as a specific marker of human Tregs. Several studies suggested that GARP expression in Tregs is post-transcriptionally regulated. To test the hypothesis that miRNAs are involved in the regulation of GARP expression, we performed an in sillico analysis to predict putative miRNAs binding sites in the 3’UTR of GARP mRNA. Six overlapping fragments of GARP 3’UTR were cloned into pEGFP-C1 and pmirGlo vectors downstream of their reporter genes. Expression of the reporter proteins after nucleofection of T cells was analyzed by flow cytometry or luciferase assay. In fact, one of the six analyzed fragments of the GARP 3’UTR was capable of down-modulating the reporter protein expression. Within this fragment, three putative binding sites were recognized by their respective miRNAs when analyzed individually. In the context of the full-length 3’UTR, however, only two of those were recognized by their miRNAs. Mutation of these sites abrogated the respective miRNA recognition confirming the specificity of the binding to GARP 3’UTR. Together, we identified and characterized an miRNA regulation locus in the GARP 3’UTR, confirming the hypothesis of post-transcriptional regulation of GARP expression. The involvement of this site into regulation of GARP expression in Tregs still needs to be investigated.
Immune dysregulation by psychological distress (113.26)
Authors: Mathews Herbert , Janusek Linda 
Published: January 2023

Abstract
The molecular basis for the immune dysfunction that accompanies psychological distress is unknown. The purpose of this study was to determine whether epigenetic modifications underlie this immune dysregulation. Women newly diagnosed with early stage breast cancer were enrolled into the study and psychological, immunological and epigenetic assessments were made at diagnosis and four months later, after completion of cancer treatment. At diagnosis women reported increased perceived stress, anxiety, and mood disturbance and the peripheral blood mononuclear cells (PBMC) of these women exhibited reduced natural killer cell activity and reduced production of interferon gamma, which contrasted with results, obtained after completion of treatment. At the epigenetic level, the PBMC of these women at diagnosis exhibited distinct epigenetic patterns, with reduced nuclear acetylation of histone residues H4-K8 and H4-K12, as well as reduced phosphorylation of H3-S10, when compared to PBMC derived after the completion of treatment. PBMC function (natural killer cell activity and interferon-gamma production) associated with nuclear acetylation and phosphorylation status of these histone residues. These findings demonstrate associations among PBMC nuclear epigenetic patterns and the immune dysregulation that accompanies psychosocial distress.
Transcription regulation of human NCR1/NKp46, an activating NK cell receptor (113.4)
Authors: Lai Chiehmin Benjamin , Cheng Grace , Moradian Annie , Morin Gregg , Mager Dixie 
Published: January 2023

Abstract
Natural Killer (NK) lymphocytes are innate immune cells, mainly known to eliminate cancerous and virus infected cells. The NCR1/NKp46 receptor is expressed specifically in the NK lineage. Activation of NK effector functions results when the receptor binds viral haemagglutinin or unidentified tumor ligands. Knockout studies have shown that the molecule is indispensible in the control of influenza infection, lymphoma growth, and the development of type I diabetes. Yet the molecular basis behind the specificity of NCR1 expression is unknown. We seek to uncover the genetic and epigenetic mechanisms that regulate human NCR1 transcription. Comparative genomics and transient luciferase assays suggest that crucial cis-regulatory elements are found within 300bp upstream of the gene. Within this proximal region, luciferase experiments also indicate the presence of a basal, non-specific promoter as well as a tissue-specific regulatory switch. Through bioinformatics and transcription factor RNA expression screens, RUNX3 was identified as a probable regulator of the switch. Chromatin immunoprecipitation (ChIP) studies were conducted to confirm RUNX3 binding in NK cells. A proteomics approach is currently underway to identify additional factors. Finally, preliminary ChIP data hints at transcriptional control by histone 3 lysine 4 methylation in blood lineages.
IFN-γ protects from IL-17 mediated lethal encephalomyelitis independent of neutrophils (114.4)
Authors: Savarin Carine , Stohlman Stephen , Cua Daniel , Bergmann Cornelia 
Published: January 2023

Abstract
Immunodeficient SCID recipients of virus-primed memory CD4 T cells survive CNS infection by neurotropic coronavirus (JHMV), whereas IFN-γ deficient (GKO) donor CD4 T cells substantially increase morbidity. Control of virus replication and demyelination are similar in both recipients. However, distinct from wild type (wt) CD4 T cell recipients, GKO recipients were characterized by massive CNS neutrophil infiltration and detection of IL-17 mRNA. To determine if the lack of IFN-γ is directly correlated to rapid mortality, wt recipients were depleted of IFN-γ. Surprisingly, anti-IFN-γ treatment did not accelerate mortality despite substantially increasing CNS neutrophils. Accelerated mortality was only observed in recipients which were deficient in IFN-γ and expressed IL-17 mRNA in the CNS. Confirming IL-17 as the pathogenic mediator, inhibition of IL-17 in GKO recipients significantly decreased mortality. Moreover, co-transfer of wt with GKO donor CD4 T cells overcame the lethal phenotype, albeit without reducing IL-17 transcription. Survival of co-transferred SCID recipients was IFN-γ dependent, suggesting that IFN-γ afforded protection by inhibiting detrimental IL-17 protein responses, rather than IL-17 mRNA. Together these data demonstrate that IL-17, in the absence of IFN-γ, can accelerate mortality during viral encephalomyelitis by a mechanism independent of the magnitude of CNS neutrophil infiltration and reversible by IFN-γ.
IL-17A, IL-17C and IL-17 receptor A are involved in atherogenesis in apolipoprotein E-deficient mice. (114.7)
Authors: Galkina Elena , Phillips Tracy , Butcher Matthew 
Published: January 2023

Abstract
Atherosclerosis is a disease of large arteries that is characterized by the formation of atherosclerotic plaques in the arterial wall and the immune response accompanies this process. The pro-inflammatory conditions of atherogenesis promote Th17 and IL-17A+γδ+ T cell generation in atherosclerosis-prone Apolipoprotein E (Apoe-/-) deficient mice, however, the role of these cells are controversial. To examine the role of IL-17A in atherogenesis, we have generated IL-17A-deficient Apoe-/- (Il17a-/-Apoe-/-) and IL-17 receptor A-deficient Apoe-/- (Il17ra-/-Apoe-/-) mice. Western diet (WD)-fed Il17a-/-Apoe-/- and Il17ra-/-Apoe-/- mice had reduced plaques compared to diet matched Apoe-/- controls. The absolute number of aortic Th1, Th17, macrophages, and neutrophils were reduced in Il17a-/-Apoe-/-, Il17ra-/-Apoe-/- aortas, and corresponded with diminished expression of multiple aortic chemokines and cytokines. In contrast, the expression of IL17C mRNA was elevated in Il17a-/-Apoe-/- and Il17ra-/-Apoe-/- mice. Flow cytometric analysis of Il17a-/-Apoe-/-, Il17ra-/-Apoe-/- spleens and aortas revealed elevated levels of IL17C+ T cells compared to Apoe-/- mice. Ex vivo treatment of Apoe-/- and Il17ra-/-Apoe-/- aortas with IL-17C strongly promoted monocyte adhesion and aortic CXCL1 expression. These results suggest that IL17A, IL17RA and IL17C play a pro-atherogenic role through the induction of aortic chemokines and the recruitment of leukocytes to atherosclerotic lesions.
Innate interleukin-22 confers protection during acute liver infection (114.8)
Authors: Zenewicz Lauren , Pedra Joao , Booth Carmen , Fikrig Erol , Flavell Richard 
Published: January 2023

Abstract
Interleukin-22 (IL-22) is an important cytokine in the regulation of tissue responses during inflammation. This molecule is highly expressed by lymphoid tissue inducer (LTi)-like cells, which are found in lymphoid tissues such as those of the tonsils or gastrointestinal tract. The functional significance of these innate immune cells and whether these cells are present in other tissues, such as the liver, has not been well characterized. In this study, we have identified a population of RORγt-dependent LTi-like cells in the liver that secrete IL-22 upon stimulation with IL-23. To examine the role of innate derived IL-22 in liver immune responses, we utilized the obligate intracellular bacterium Anaplasma phagocytophilum. This important emerging tick-borne pathogen provokes a host innate immune response-driven hepatitis. Innate IL-22 provided protection to this liver injury as well as from bacterial infection. Additionally, A. phagocytophilum infection led to hepatocyte upregulation of the IL-22 receptor in an IL-22 dependent manner. Modulation of the IL-22 signaling pathway during infection may allow for optimal tissue responses to protect the host. Thus, IL-22 derived from LTi-like cells plays an important protective role in acute liver infection.
Regulatory T cells induced by GM-CSF suppress disease severity and selectively inhibit acetylcholine receptor-stimulated T cell responses in experimental myasthenia gravis (115.1)
Authors: Sheng Jianrong , Prabahakar Bellur , Meriggioli Matthew 
Published: January 2023

Abstract
We and others have demonstrated the ability of granulocyte-macrophage colony-stimulating factor (GM-CSF) to induce and maintain semi-mature, tolerogenic DCs in vivo, and have shown that treatment could suppress autoimmunity by inducing CD4+CD25+ regulatory T cells (Tregs). In the current study, we have confirmed the critical role of Tregs in the therapeutic effects of GM-CSF both in vitro and in vivo utilizing extensive adoptive transfer experiments. Specifically, we show that Tregs from GM-CSF treated EAMG mice transferred to animals with EAMG suppress clinical disease more potently than equal numbers of Tregs from untreated mice. In addition, GM-CSF-induced-Tregs (GM-CSF iTregs) from EAMG mice potently and specifically suppress T cell proliferation induced by AChR, but do not alter T cell proliferation in response to irrelevant antigens to any greater extent than Tregs obtained from naive mice (so called natural Tregs [nTregs]). These results are consistent with the hypothesized mechanism of action of GM-CSF involving the mobilization of “semimature” dendritic cell precursors which, upon antigen (AChR) capture, initiate a suppression of the anti-AChR immune response, predominantly through the activation of AChR-specific iTregs. These preclinical findings provide important knowledge that may allow for clinical application of GM-CSF or related molecules to the treatment of human MG in the future.
Protective Tnfrsf9 haplotype mediates increased survival of functionally superior CD137+ T regulatory cells in type 1 diabetes (115.16)
Authors: Kachapati Kritika , Adams David , Wu Yuehong , Mittler Robert , Ridgway William 
Published: January 2023

Abstract
CD137 is a T cell costimulatory molecule that increases cell survival and promotes cytokine production, and is a candidate gene (Tnfrsf9) in NOD.B10 Idd9.3 congenic mice. We have shown that Tregs constitutively expressing CD137 are the target of anti-CD137 antibody that protects NOD from diabetes. Here, we show that NOD.B10 Idd9.3 CD137pos, but not CD137neg or NOD, Tregs have increased in vivo survival. Mixed bone marrow chimera mice made with NOD and NOD.B10 Idd9.3 bone marrow showed that increased survival in Tregs expressing the B10, but not NOD, Tnfrsf9 allele was an intrinsic cellular effect. NOD.B10 Idd9.3 CD137pos Tregs also express more anti-apoptotic Bcl-xl than NOD Tregs. To understand the impact of increased survival of CD137pos Tregs on disease, we performed functional studies that showed that CD137pos Tregs are significantly more suppressive than CD137neg Tregs in-vitro. We show that CD137pos Tregs, not CD137neg Tregs or T effectors, are the primary producers of the alternatively spliced CD137 isoform, soluble CD137. Soluble CD137 directly suppressed effector T cells by binding to CD137L on T cells in an APC independent assay. The increased suppression of CD137pos Tregs was associated with increased production of soluble CD137 and these studies show the importance of CD137pos Tregs in T1D.
Sex hormones and gender influence the expression of Foxp3 and regulatory T cells in SLE patients (115.18)
Authors: Dinesh Ravi , Hahn Bevra , Singh Ram 
Published: January 2023

Abstract
Regulatory T cells have been implicated in the maintenance of immune tolerance. Whether sex hormones and gender influence the expression of FoxP3 and regulatory T cells remain obscure. We provide the first evidence in this study that numbers and percent expression of regulatory T cells are significantly reduced in healthy females compared to healthy males. We found that both CD4+CD25+hi and CD8+CD25hi+ subsets of healthy males had 3-4-fold higher Foxp3 mRNA compared to healthy females. Estrogen increases proinflammatory cytokines and plasma estradiol positively correlated with IL-21 in SLE pts. Levels of estradiol positively correlated with SLEDAI score. Testosterone level was decreased in SLE women compared to healthy women. Furthermore, testosterone significantly increased FoxP3 expression in CD4+CD25hi cells from women with SLE. Plasma concentrations of testosterone positively correlated with the expression of FoxP3 in Treg. These data demonstrate that women may be more susceptible than men to SLE and other autoimmune diseases in part because many healthy women have fewer regulatory T cells and less FoxP3 expression. In addition, women with SLE, compared to healthy women, seem to have less ability to generate CD4+ Treg in response to physiologic concentrations of 17b-estradiol, whereas testosterone metabolite increases the generation of Tregs. These data suggest that gender and sex hormones influence susceptibility to SLE via their effects on Treg and Foxp3 expression.
Auto-reactive exTreg cells are generated during the initiation of autoimmune inflammation. (115.23)
Authors: Bailey-Bucktrout Samantha , Zhou Xuyu , Rosenthal Wendy , Bluestone Jeffrey 
Published: January 2023

Abstract
The onset of autoimmunity is associated with a reduced frequency of Foxp3+ T regulatory (Treg) cells, or reduced Foxp3 expression. We have observed that Tregs can lose Foxp3 under homeostatic conditions to form exTreg cells, and that islet-specific exTreg cells induced autoimmune type 1 diabetes (T1D). ExTreg generation in the islets correlates with low IL-2Rα (CD25) expression, and IL-2 complexes directed at Treg cells can rescue T1D. Unstable Foxp3 expression may weaken the ability of the Treg compartment to suppress effectors, and, exTregs can themselves be pathogenic. In this study, we used class II tetramers conjugated with myelin oligodendrocyte peptide 38-49 (MOG38-49) to analyze the myelin-reactive potentially pathogenic CD4+ conventional effector T cells and Treg cells during experimental autoimmune encephalomyelitis (EAE). We observed exTreg generation from Tregs enriched for MOG38-49-specificity, and this correlated with EAE progression. CD25 expression was high on Tregs and exTregs in the inflamed central nervous system, so low CD25 cannot explain Foxp3 instability in this setting. This is the first description of auto-reactive Treg cells within a normal T cell repertoire losing Foxp3 expression during the onset of autoimmunity. It supports the hypothesis that Tregs are enriched for self-reactivity, and that unstable Tregs are associated with progressive autoimmune disease.
Blockade of Programmed death-1 induces functional CD4+ regulatory T cells to resist apoptosis in (New Zealand Black x New Zealand White)F1 lupus-prone mice (115.25)
Authors: Wong Maida , La Cava Antonio , Hahn Bevra 
Published: January 2023

Abstract
PD-1 is a negative regulatory signal in T cells. We hypothesize that regulation of PD-1 signaling is required for maintenance of functional regulatory T cells (Treg) and subsequent control of autoimmunity in BWF1 mice, and that regulatory capacity of the cells is sustained in part by resistance to apoptosis, resulting in Treg survival. By toleration with an artificial peptide pCons, we have shown induction of CD4+ and CD8+ Foxp3+Treg with reduced of PD-1 expression decrease anti-dsDNA and nephritis and prolong survival. The same outcomes are observed when PD-1 expression is blocked by a neutralizing antibody. Here, anti-PD1 or pCons treatments maintained total numbers of functional suppressive Foxp3+CD4+CD25+ T cells between 10 and 40 weeks of age. The decline in IL-2 was significantly delayed by anti-PD1, and TGF-β production was increased. These CD4+Treg were resistant to spontaneous apoptosis, suppressed CD4+CD25- T cell proliferation, and induced apoptosis in B cells. In particular, Fas and FasL are two candidate molecules in the apoptotic pathways that were upregulated in splenic CD4+Treg upon pCons-tolerization or PD-1 blockade. To conclude, PD-1 is central in control of some regulatory T cells that suppress autoimmunity; their PD-1 expression may need fine tuning to permit the cells to survive and retain suppressive capacities. A mechanism by which PD-1 sustains these Treg is by reducing their susceptibility to apoptosis, which may relate to altering Fas/FasL pathway.
Host-derived CD4+ T cells protect lethally irradiated B6.g7 mice from stem cell mediated transfer of autoimmunity. (115.26)
Authors: Rajasekaran Narendiran , Wang Nan , Truong Phi , Rinderknecht Cornelia , Beilhack Georg , Shizuru Judith , Mellins Elizabeth 
Published: January 2023

Abstract
In the K/BxN mouse model of inflammatory arthritis, T cells carrying a transgenic TCR initiate disease by helping B cells to produce arthritogenic anti-GPI (glucose-6- phosphate isomerase) autoantibodies. We found that lethally-irradiated lymphocyte-deficient B6.g7 (I-Ag7+) Rag-/- mice reconstituted with K/BxN HSC (ckit+Lin-Sca-1hi) exhibit arthritis by week 4 and have anti-GPI Ab levels comparable to K/BxN mice. The normal B6.g7 mouse recipients of KBN HSC, however, showed only a mild arthritis with limited extent and duration. Titers of anti-GPI Abs in reconstituted B6.g7 mice were ~60 fold lower than in K/BxN mice. To investigate the basis of this attenuated autoimmunity, we examined the chimerism in the reconstituted B6.g7 mice. Although the B cell and myeloid compartments in blood and spleen had 98%±0.1 donor-derived cells, the CD4+ T cells were only 12%± 2.5 donor-derived. Further, host-derived CD4+ T cells in the reconstituted B6.g7 mice were 18%±3.5 CD25+FoxP3+ Treg cells compared to 8%±1.76 Tregs in donor-derived CD4+ T cells (P&lt;0.024). Notably, attenuation of autoimmune diabetes and high percentage of host-derived Tregs (hTreg) were also observed when B6.g7 mice were reconstituted with HSCs from BDC2.5 transgenic mice. The hTreg were functional in vitro in standard assays. Our findings show that despite myeloablation, hTreg emerge in these mice and attenuate autoimmunity.
ITAM signaling negatively regulates dendritic cell function via SOCS-1 (116.19)
Authors: Ito Hiroaki , Lau Laura , Hamerman Jessica 
Published: January 2023

Abstract
Dendritic cells (DCs) play a crucial role in both the innate and adaptive immune system. DCs use several receptor systems to recognize pathogens, including Toll-like receptors (TLR). We have found that two immunoreceptor tyrosine-based activation motif (ITAM) adaptors (DAP12 and FcRγ) negatively regulate TLR responses in DCs, however the precise mechanism by which ITAM signaling suppresses TLR responses remains to be elucidated. Here, we show that aberrant SOCS-1 expression was found in ITAM signaling-deficient DCs. SOCS-1 is a well-described suppressor for TLR signaling as well as cytokine signaling, including signaling from the IFN-γ and IFN-α/β receptors. We found decreased SOCS-1 expression in DAP12/FcRγ-deficient BM-derived DCs (BMDCs) in comparison with WT BMDCs before and after TLR stimulation at both mRNA and protein levels. MHC class II expression on DAP12/FcRγ-deficient BMDCs was higher than that of WT BMDCs even under steady state conditions, similar to SOCS-1 deficient DCs. Consistent with the decrease of SOCS-1 expression in DAP12/FcRγ-deficient BMDCs, STAT-1 phosphorylation was increased in DAP12/FcRγ-deficient BMDCs upon IFN-γ stimulation in comparison with WT BMDCs. These results suggest that ITAM signaling positively regulates SOCS-1 expression to inhibit DC activation.
A negative regulatory role for Traf3 in DNA-induced type I interferon production (116.21)
Authors: Dev Anurupa , Wang Yaya , Ghaffari Amirali , Cheng Genhong 
Published: January 2023

Abstract
While the adaptor protein TRAF3 is known to be a positive regulator of the type I interferon (IFN) response to RNA-mediated TLR and RLR activation, its role in DNA-induced IFN induction is not clear. Here we provide evidence of a negative regulatory role for TRAF3 in the IFN response to intracellular DNA. Traf3-/- MEFs infected with HSV-1 or stimulated with B-form DNA produce elevated levels of type I IFNs, and subsequently have a significant reduction in HSV-1 viral replication and production as compared to wildtype cells. Interestingly, cells lacking TRAF2 or cIAP1/2, components of the TRAF3-containing complex required for suppression of noncanonical NF-κB activation, were also found to hyperinduce IFN upon stimulation with B-DNA. Further studies indicate that components of the noncanonical NF-κB signaling pathway interact and also synergize with TBK1 in IFN production, and activating this pathway provides protection against HSV-1 infection both in vitro and in vivo. Thus, our studies suggest that TRAF3 plays opposing roles in regulating pathogenic DNA versus RNA-induced IFN responses.