bluuebunny/crossref_metadata_2025_split huggingface dataset:
Melanocortin 5 receptor expressed by APC mediates activation of Treg cells during experimental autoimmune uveoretinitis (166.21)
Authors: Lee Darren , Taylor Andrew 
Published: January 2023

Abstract
We previously showed that IRBP-specific memory Treg cells (Tregs) emerge in the spleen of experimental autoimmune uveoretinitis (EAU) recovered mice and are necessary to protect from a memory immune response to IRBP. Induction of these memory Tregs require melanocortin 5 receptor (MC5r), and APC also from EAU recovered mice. We investigated if the T cell or the APC requires MC5r in the induction of memory Tregs that emerge during EAU resolution. EAU was induced in C57BL/6 wild type and MC5r(-/-) mice with IRBP, the spleen cells were collected througout EAU to assay for IRBP stimulated T cell cytokine production of IFN-γ, IL-17, and TGF-β. We observed a MC5r dependent shift in the cytokine profile from effector cytokines, Th1 and Th17, in the beginning of EAU to regulatory. MC5r was required for a consistent increase in TGF-β production through the course of EAU, continuing through resolution. Isolated APC from the spleens of EAU-recovering mice were able to convert IRBP-specific MC5r(-/-) Th1 cells into Tregs, that are capable of suppressing EAU when adoptively transferred into mice with EAU. We have found that during the course of EAU a nonconventional APC emerges in the spleen. This APC requires expression of MC5r to promote induction of memory Tregs. Therefore, stimulation of the melanocortin pathway during EAU is required for the reestablishment of immune tolerance to ocular autoantigens.
Fever regulates inflammation through microRNAs and SOCS in pulmonary epithelial cells (166.23)
Authors: Pickering Edward , Luzina Irina , Hasday Jeffrey , Atamas Sergei 
Published: January 2023

Abstract
Inflammation is often accompanied by fever, which may affect patients' survival in severe acute diseases. Pulmonary epithelium is involved in lung inflammation, and a major role for microRNAs has been suggested. To determine whether febrile temperature (FT) affects the response to inflammation at the level of microRNAs, primary small airway epithelial cells were incubated at either 37 deg C or 39.5 deg C with or without 5 ng/ml TNF-α for three hours. Total RNA was isolated, labeled, and hybridized to Affymetrix microRNA arrays. After data normalization and using a 1.5 fold change as a cutoff value, we identified 59 microRNAs levels of which changed up to 8 fold in response to FT. Also, levels of 46 microRNAs changed up to 5 fold in the presence of FT plus TNF-α. Putative gene targets for these microRNAs were identified using microRNA.org, Targetscan, and Pictar databases. Many of the identified targets are involved in inflammatory pathways, including members of the suppressor of cytokine signaling (SOCS) family SOCS1 (miR-19), SOCS2 (miR-214, -139, -194), SOCS3 (miR-19, -30), SOCS4 (miR-27, -34, -125), SOCS5 (miR-18, -24, -25, -92, -130), and SOCS6 (miR-15, -17, -19, -20, -23, -27, -30, -106, -128, -130). Levels of all 10 microRNAs potentially targeting SOCS6 were decreased by both FT and TNF-α activation, with an additive effect of these two activators on miR-15, -30, and -130. Thus, innate inflammatory mechanisms involve broad microRNA-mediated regulation of SOCS by fever.
Host immunological conditions that determine status of Helicobacter pylori as pathogenic or commensal bacterium (166.26)
Authors: Wendelsdorf Katherine , Cabo Adria , Hoops Stefan , Hontecillas Raquel , Bassaganya-Riera Josep 
Published: January 2023

Abstract
H. pylori is a leading cause of peptic ulcer, gastric lymphoma and adenocarcinoma. In spite of being a highly prevalent bacterium in the gastric mucosa, only 15 % of carriers develop overt disease. Bacterial pathogenesis is believed to arise from an interaction of strain-specific immunity-mediating capabilities and the host susceptibility. To investigate the mechanisms of immune modulation by H. pylori we have created a mathematical model of immune cells of the gastric mucosa, gastric lymph nodes and their response to H. pylori. A local sensitivity analysis suggests that, in a healthy host, the H. pylori strains that are asymptomatically tolerated are those with the ability to invade the mucous layer as well as those that inhibit the ability of epithelial cells to secrete defensin and chemoattractants. Interestingly, our model also indicates that persistence of H. pylori in the gastric mucosa is facilitated by a strain’s ability to induce secretion of inflammatory mediators in the gastric epithelium. However, H. pylori strains that induce a tolerogenic phenotype in APCs or induce cytoskeletal changes in epithelial cells are likely to elicit a pathological inflammatory response. A global sensitivity analysis revealed novel context-dependent functional interactions occurring between the host and H. pylori.
Normal development of regulatory T cells in the post natal mouse liver requires both MyD88 and TGF-β1 (166.3)
Authors: Maria Ann , Epstein Samantha , English Kathryn , Gorham James 
Published: January 2023

Abstract
Regulatory T cells (Treg) play a major role in the maintenance of immune tolerance and homeostasis. The liver microenvironment promotes immune tolerance, but very little is known about the development of the Treg compartment in liver. We examined the kinetics of Treg (FoxP3+CD4+ T cells) development in the post-natal mouse liver. Liver Tregs were first detected in liver at post-natal day 2 (P2). The Treg frequency in liver rapidly surged thereafter, peaking to 20-25% of liver CD4+ T cells at P8, over twice as frequent as in spleen (10%), and declined thereafter to reach an adult frequency of ~3% CD4+ T cells. The liver receives a large supply of its blood through the portal vein, which drains the intestine. We hypothesized that the early “surge” in liver Treg frequency occurs in response to colonization of the gut by commensal bacteria. In support of this hypothesis, the surge was partially abrogated in Myd88+/- mice and completely abrogated in Myd88-/- mice. The cytokine TGF-β1 has been previously shown to be important for several aspects of the Treg response pathway; the liver Treg surge was abrogated in Tgfb1-/- mice. We conclude that the early post-natal surge of Treg in liver is dependent on both MyD88 and TGF-β1. We suggest the following model: colonization of the newborn gut drives a surge in the liver Treg compartment, likely mediated by one or more TLR pathways, and TGF-β1 is an important effector cytokine of this response.
Generation of colitogenic Th17 CD4 T cells and experimental colitis is enhanced by IL-17+ γδ T cells (166.5)
Authors: Do Jeongsu , Visperas Anabelle , Baldwin III William , Min Booki 
Published: January 2023

Abstract
Adoptive transfer of naïve CD4 T cells into T cell deficient mice induces severe colitis, a widely used animal model to study inflammatory bowel disease (IBD) including ulcerative colitis and Crohn’s disease. Th17 cells have been implicated in the pathogenesis of T cell-mediated colitis, although cellular mechanism(s) that supports in vivo Th17 differentiation and colitis induction remains unclear. We report here that γδ T cells play critical roles in amplifying Th17 differentiation and subsequent development of colitis in mice. Following naïve CD4 T cell transfer, TCRβ-/- mice developed severe colitis with enhanced Th17 differentiation, while TCRβ/δ-/- mice showed no sign of weight loss with very mild colitis. Th17 differentiation in TCRβ/δ-/- recipients was significantly diminished compared to that in TCRβ-/- recipients. Adoptive transfer of CD4 T cells with γδ T cells fully restored colitis in TCRβ/δ-/- mice and Th17 differentiation was accordingly elevated. Surprisingly, IL-17 production by γδ T cells was found to be very important for colitogenic effect because cotransfer of CCR6+ (IL-17+) γδ T cells was sufficient to promote Th17 differentiation and colitis yet transfer of CCR6- (IL-17-) γδ T cells failed to do so. Collectively, our results demonstrate that IL-17 production by γδ T cells play a critical role in fostering in vivo Th17 differentiation and inducing colitis, implying that targeting these cells might be beneficial to treat the disease.
Epidermal ADAM17 provides barrier immunity and prevents myeloproliferative disease by regulating Notch-AP1 interaction (166.7)
Authors: Murthy Aditya , Shao Yang Washington , Guinea-Viniegra Juan , Narala Swami , Zúñiga-Pflücker Juan Carlos , Wagner Erwin , Khokha Rama 
Published: January 2023

Abstract
Epithelial cells are the major component of mucosal tissues such as the skin, gut and lungs. They are critical barriers against environmental stress factors which induce significant immunopathology. Keratinocytes in the skin may act as key decision-makers of immune cell function by directing local adaptive immune responses and hematopoietic development, however mechanisms driving epithelial:immune crosstalk are incompletely understood. The cell surface sheddase A Disintegrin and Metalloproteinase 17 (ADAM17) cleaves numerous proteins with key roles in development, stress response and inflammation. Here we show that loss of epidermal Adam17 leads to severe atopic dermatitis and myeloproliferative disease. ADAM17 deficiency in keratinocytes enhanced AP1 signaling, increasing the production of epithelial cytokines (e.g. TSLP, IL-33) to drive Th2-polarized lymphocyte activation. We also observed the release of myeloid growth factors (e.g. G-CSF), causal to myeloproliferative disease in these mice. Next, we identified that ADAM17 promotes ligand-independent Notch activation in keratinocytes, revealing a novel mechanism of Notch-AP1 interaction that abrogates stress signaling. Notably, ectopic Notch activation in the epidermis of ADAM17 deficient mice rescued local inflammation and myeloproliferation. Thus Notch activation by ADAM17 in keratinocytes antagonizes AP1-induced inflammation, thereby establishing a mechanism of epithelial:immune crosstalk.
Synovial fluid cells in proteoglycan-induced arthritis contain a myeloid-derived suppressor population (167.21)
Authors: Egelston Colt , Besenyei Timea , Tryniszewska Beata , Rauch Tibor , Glant Tibor , Mikecz Katalin 
Published: January 2023

Abstract
Joint damage in rheumatoid arthritis (RA) is largely mediated by synovial fluid (SF) neutrophils. In proteoglycan (PG)-induced arthritis (PGIA), an autoimmune mouse model of RA, SF cells show high expression of the myeloid lineage markers CD11b and Gr-1. The effects of this neutrophil-like SF cell population on the activation of dendritic cells (DCs) or T cells have not been studied in RA or its animal models. We co-cultured SF cells of PGIA mice with bone marrow-derived DCs, and found that levels of MHC II and CD86 expression by DCs decreased significantly in the presences of SF cells. To determine if SF cells also reduced the antigen (Ag)-presenting capacity of the DCs, we added naïve PG-specific TCR transgenic T cells and cognate Ag to the co-cultures. T cells cultured in the presence of SF cells and Ag-loaded DCs showed significant decreases in CD69 expression and proliferation compared to T cells cultured with Ag-loaded DCs only. Arginase-1, a marker of myeloid-derived suppressor cells (MDSCs) was upregulated at both transcriptional and protein levels in SF cells. Expression and activity of arginase-1 were also elevated in spleen cells of arthritic mice as compared to spleen cells of naïve non-arthritic mice. Our results suggest that SF cells in the arthritic joints and spleens of mice with PGIA contain a population of MDSCs, which might have the capacity to suppress autoreactive T cell responses and thus accelerate the resolution of joint inflammation.
A crucial role of IL-6 in B cell tolerance induction after antigen activation (167.6)
Authors: Yan Yi , Diamond Betty 
Published: January 2023

Abstract
Receptor editing, clonal deletion and anergy are the key components of the central tolerance. It is well characterized that receptor editing plays the most important role among the three mechanisms. We recently identified a post germinal center tolerance check point, where receptor editing is re-induced to diminish the autoreactive B cells generated by class switching and somatic hypermutation. Here we demonstrate that this de-novo re-induction of the recombinase RAG gene in antigen-activated B cells is reduced by neutralization of IL-6. Serum level of autoreactive anti-dsDNA antibodies is increased in mice immunized with a peptide mimetope of dsDNA if they are given antibodies to IL-6 to reduce receptor editing. The same effect is observed in mice haploid for IL-6 when compared to WT mice. This dependence on IL-6 is B cell intrinsic, as demonstrated in adoptive transfer experiments when B cells from either WT mice or IL-6+/- mice were reconstituted in uMT mice. Our data reveal a novel but crucial role of IL-6 in regulation of the B cell autoimmunity, and show that Il-6 serves a regulatory function as well as being proinflammatory.
Estrogen upregulates cyclic AMP response element modulator alpha expression and downregulates interleukin-2 production by human T lymphocytes (167.8)
Authors: Moulton Vaishali , Holcomb Dana , Tsokos George 
Published: January 2023

Abstract
Systemic lupus erythematosus (SLE) is an autoimmune disease with a complex multifactorial etiopathogenesis and primarily afflicts women. T lymphocytes play a critical role in disease pathogenesis and display abnormal gene expression and function. A major defect is their inability to produce the vital cytokine interleukin-2 (IL-2) due to defects in IL2 transcription. We previously showed that the expression of the transcriptional repressor cyclic AMP response element modulator alpha (CREMα) is increased in SLE T cells, and contributes to reduced IL-2 production. While estrogen is implicated in the onset and exacerbation of SLE, the precise nature of molecular events regulated by estrogen in immune cell function is not well understood. Here we asked whether estrogen regulates the expression of CREMα in human T lymphocytes. We show that exposure of human T cells to 17- β-estradiol leads to increased CREMα mRNA expression, and this increase appears to be estrogen receptor dependent. We show that the increased expression of CREMα is due to increased transcriptional activity of the CREM promoter, and is mediated by increased expression and binding of the Sp1 transcriptional activator. We further show that estrogen treatment leads to decreased IL-2 production by T cells. Our results show that estrogen can modulate the expression of CREMα and lead to IL-2 suppression in human T lymphocytes, thus revealing a molecular link between hormones and the immune system in SLE.
Foxp3+ regulatory T cells promote Th17 development in vivo through regulation of IL-2 (168.16)
Authors: McGeachy Mandy , Cua Daniel , Hammerling Gunther , Li Ming , Hochweller Kristin , Gutcher Ilona , Haines Christopher , Chen Yi 
Published: January 2023

Abstract
Th17 development is driven by multiple cytokines, including TGF-β. Regulatory T cells (Tregs) promote Th17 development through production of TGF-β in vitro. However their role in vivo remains unclear, particularly since Tregs inhibit inflammation in many models of autoimmunity where Th17 cells are active. Using mice expressing Diphtheria toxin receptor under control of the Foxp3 promoter, Foxp3+ Tregs were depleted in adult mice during in vivo Th17 priming. Treg depletion resulted in a reduced frequency of antigen-specific IL-17 producers in draining lymph nodes and blood, correlating with reduced inflammatory skin responses. In contrast, Tregs did not promote IL-17 after initial activation stages. Treg production of TGF-β was not required for Th17 promotion, neither was suppression of Th1-associated cytokines. Rather, regulation of IL-2 availability and resultant signaling through CD25 and pSTAT5 by Tregs was found to play an important role.
A role of TGFβ in p53-induced CD28-dependent T cell apoptosis (168.18)
Authors: Takami Mariko , Iwashima Makio 
Published: January 2023

Abstract
Naturally arising CD4+CD25+ Tregs (nTregs) are essential for maintaining immune homeostasis and peripheral tolerance. The balance between nTregs and conventional T cells appears to play a significant role in immune regulation. The majority of nTregs are considered to recognize antigen peptides derived from self tissues and are predicted to receive continuous antigen stimulation, but regulation of Treg growth and survival against activation-induced cell death (AICD) in vivo is not well-understood. Recently, we reported a novel form of apoptosis (p53-dependent CD28- induced T cell apoptosis: PICA) which is distinguishable from classical AICD. We demonstrated that conventional T cells undergo massive p53- induced apoptosis when stimulated by anti-CD3 and anti-CD28 antibodies coated on flat surface. Most importantly, nTregs survive and expand effectively under the same culture conditions, showing that there is a different survival/ apoptosis mechanism between nTregs and non-Tregs in regards to PICA. Here, we report that transforming growth factor β (TGFβ) signaling is required for survival of Tregs against PICA and the presence of the exogenous active form of TGFβ renders conventional T cells resistant to PICA. TGFβ-mediated survival of nTregs is in part mediated by downmodulation of a pro-apoptotic protein, Bim, by a posttranscriptional mechanism. Together, the data show that TGFβ plays a critical role in PICA and may contribute to the maintenance of Tregs: non-Tregs balance.
Interleukin-17 overcomes inhibition of Th1 immune responses following mycobacterial exposure (168.2)
Authors: Gopal Radha , Lin Yin-Yao , Obermajer Nataša , Kalinski Pawel , Khader Shabaana 
Published: January 2023

Abstract
Tuberculosis (TB) caused by the intracellular pathogen Mycobacterium tuberculosis, remains a worldwide health problem. Generation of effective T helper cell type 1 (Th1) responses are required for immunity against intracellular bacteria. However, multiple bacteria successfully inhibit the direct pathway of induction of Th1 responses, promoting the production of factors such as prostaglandin E2 (PGE2) and interleukin (IL-10), that suppress IL-12 and interferon gamma (IFNγ) production. Here, in a model of Mycobacterium bovis Bacille Calmette Guerin (BCG) vaccination, we demonstrate that a nominal Th1-suppresive factor, PGE2, can promote an alternative pathway of induction of Th1 immunity that is mediated by IL-23-dependent IL-17 induction. We show that PGE2 limits early Th1 responses via IL-10 production but also drives Th17 responses via IL-23 production. IL-17 then functions to overcome PGE2-IL-10-mediated Th1 inhibition and drive Th1 immunity following BCG exposure. Therefore, we demonstrate that PGE2-induced IL-17 response allows overcoming BCG-induced PGE2- and IL-10-mediated inhibition of IL-12 production and Th1 responses. The currently described alternative IL-17-dependent pathway of induction of Th1 immunity helps to understand the complex role of PGE2 in the regulation of immune responses and helps to design new therapeutic approaches in chronic intracellular infections.
Neuropilin-1 is a potent negative regulator of CD4 T cell responses (168.21)
Authors: Bynoe Margaret , Solomon Benjamin , Mueller Cynthia , Chae Wook-Jin , Alabanza Leah 
Published: January 2023

Abstract
Neuropilin-1 (Nrp1) is a type-1 transmembrane cell surface molecule originally identified for its role in neuronal development. We have found that Nrp1 is highly expressed on CD4 T cells from mice that had been epicutaneously immunized with a myelin antigen, myelinoligodendrocyte glycoprotein (MOG), and confer dominant tolerance against experimental autoimmune encephalitis (EAE, the animal model for multiple sclerosis). Recently, Nrp1 has been implicated in several aspects of immune function including maintenance of the immune synapse and development of regulatory T cells (Treg). Here, we identify Nrp1 as a critical negative regulator of CD4 T cell effector function. We demonstrate that CD4 T cells lacking Nrp1 (via conditional deletion) exhibit preferential Th17 lineage commitment, are hyperproliferative and produce high levels of proinflammatory cytokines. Mice with conditional deletion of Nrp1 in CD4 T cells develop fulminant EAE that can be inhibited by blocking Th17 cell development. Conversely, mice receiving CD4 T cells that are retrovirally transduced with Nrp1 do not develop EAE. Further, Nrp1-expressing CD4 T cells are potent suppressors of CD4 T cell effector function. This suppression is independent of FoxP3 and can be inhibited by blockade of TGF-beta but not by IL-10 blockade. These findings are the first to demonstrate a specific regulatory role for Nrp1 in immune regulation and provide the impetus for the use of Nrp1 as a therapeutic immune modulator.
Regulatory T cells suppress immune activation under homeostatic conditions in adult mice by antigen-independent and -dependent mechanisms (168.22)
Authors: Punkosdy George , Shevach Ethan 
Published: January 2023

Abstract
Regulatory T cells (Treg) maintain immune homeostasis by preventing excessive immune activation. This is clear in neonates since mice lacking Treg (scurfy) develop multi-organ autoimmunity early in life. However, the mechanism by which Treg maintain homeostasis in adults is less clear. We show, using “depletion of Treg” (DEREG) mice, that Treg depletion in adult mice results in the immediate acquisition of a CD44hi phenotype on the vast majority of conventional (CD4+Foxp3-) T cells. CD44 expression is a characteristic of newly activated as well as memory phenotype (MP) T cells, so we sought to determine whether the increase in CD44hi cells was the result of naïve cell activation or expansion of MP cells. The proliferative rate of MP cells increased dramatically during the 72-hour period following Treg depletion as determined by Ki-67 positivity and BrdU incorporation. This expansion was not inhibited by the administration of anti-MHC Class II antibodies, suggesting that the mechanism was antigen-independent. Naïve T cells also developed a CD44hi phenotype following Treg depletion but via an antigen-dependent mechanism. Activation of OT-II T cells transferred into DEREG-RIP/OVAlo mice was markedly enhanced by Treg depletion while transfer into wild-type DEREG mice did not result in activation regardless of Treg depletion. Collectively, these results demonstrate that Treg control immune activation under homeostatic conditions by antigen-independent and -dependent mechanisms.
B7-CTLA4 reverse signaling is responsible for regulatory T cell-induced suppression of dendritic cells (168.23)
Authors: Kowalczyk Aleksandra , Zhang Li 
Published: January 2023

Abstract
CD4+CD25+Foxp3+ regulatory T cells (Treg) are essential for maintaining immune tolerance and homeostasis. It has been shown that natural Treg can inhibit up-regulation of costimulatory molecules on dendritic cells (DC). However, the mechanism leading to this phenomenon has not been elucidated. Whether inducible Treg (iTreg) also possess this function has not been previously investigated. Here, we demonstrate that iTreg could inhibit LPS-induced DC maturation and mediate down-regulation of CD80 and CD86 on mature DC. This process is CTLA4-dependent as Treg isolated from CTLA4-/- mice did not down-modulate B7 molecules on DC. Furthermore, CTLA4Ig, but not CD28Ig, mimicked iTreg action. Down-regulation of CD80/CD86 was not due to endocytosis or protease-dependent shedding, but rather to a reverse signaling through B7. CTLA4Ig treatment decreased CD80 and CD86 transcription, as well as NFκB activity upon LPS stimulation. Interestingly, both CTLA4Ig and co-incubation with iTreg induced a profound STAT3 phosphorylation in DC, whereas no significant effect on the proximal NFκB pathway was observed. Inhibition of STAT3 activation partially abolished CTLA4Ig-induced CD80/CD86 down-modulation suggesting involvement of this molecule in the observed process. Our data reveal a novel signaling pathway by which Treg can suppress DC via reverse signaling, and may provide new opportunities for therapies targeting costimulatory pathways.