bluuebunny/crossref_metadata_2025_split huggingface dataset:
Antibiotic treatment causes a reduction in antigen-specific T cell memory and increased susceptibility to secondary infection
Authors: Benoun Joseph M , Labuda Jasmine C , Fogassy Zachary N , Pham Oanh , Pham Quynh-Mai , Puddington Lynn , McSorley Stephen J 
Published: January 2023

Abstract
Salmonella enterica serovar Typhi causes recurrent and relapsing infection in antibiotic-treated individuals, suggesting that rapid bacterial clearance hinders the development of adaptive immunity. We have developed an antibiotic-treatment model in mice to examine this issue. This model demonstrates poor secondary protection after antibiotic treatment and allows the use of antigen-specific reagents to examine this issue in detail. Infection with Salmonella Typhimurium (BRD509-2W1S) caused expansion of Salmonella-specific CD4 T cells that were detected in peripheral blood, lymphoid tissues, and various non-lymphoid tissues. In contrast, antibiotic-treated mice had lower CD4 clonal expansion that persisted for months after infection. This reduced clonal frequency of Salmonella-specific CD4 T cells correlated with diminished protective immunity to secondary infection. In order to examine the protective contribution of circulating and non-circulating CD4 T cells, parabiosis experiments were performed whereby mice previously infected with BRD509-2W1S were paired with naïve mice for 30 days. Previously infected mice were more capable of controlling secondary infection compared to naïve parabionts or naïve control mice, however naïve parabionts were partially protected, indicating the requirement of both tissue resident and circulating cellular populations. Current experiments are underway to restore full protection during antibiotic intervention. Greater understanding of how antibiotics hinder CD4 memory development may allow for therapeutics to boost protective immunity to secondary or relapsing Salmonella infections. (Funding: NIH 5P01AI056172-09)
Type-1 interferon induced cross-regulation of IL-10 function: a novel mechanism in type 1 diabetes development
Authors: Lozano Marcos Iglesias , Arun Anirudh , Lam Brandon , Lee W.P. Andrew , Brandacher Gerald , Raimondi Giorgio 
Published: January 2023

Abstract
Type 1 Diabetes (T1D) is caused by T cell-mediated destruction of insulin-producing beta cells of the pancreas. The “fertile field” hypothesis of T1D proposes that in a genetically predisposed individual, an inflamed environment prompts the organ towards autoimmunity. In this study, we tested whether chronic and localized accumulation of type I interferons (TI-IFNs) creates a “fertile field” that releases diabetogenic T cells from immuneregulation. In vitro incubation of mouse T cells with IFN-beta renders memory and regulatory T cells with a dramatic defect in the production of phospho-STAT3 in response to the regulatory cytokine IL-10 (but not to IL-6). This resulted in prevention of upregulation of IL-10 induced genes. Altered signaling was NOT caused by reduction of IL-10 receptor expression, nor induction of Suppressor of Cytokine Signaling (SOCS) 1 or 3. Instead, microarray analysis suggested a novel role for the transcription factor STAT1 in dampening IL-10 signaling. IFNbeta induces STAT1 expression causing a reversal of the intracellular STAT1/STAT3 protein ratio that favors a competitive role of STAT1. In agreement, STAT1-KO T cells exposed to IFN-beta did not show any defect in IL-10 signaling. In diabetes-prone NOD mice we discovered a persistent reduction of IL-10 signaling in Tmem and Treg restricted to pancreatic and mesenteric lymph nodes (correlating with the reported local accumulation of TI-IFNs). Treatment of these mice with an IFNRA blocking antibody (that delays the onset and reduces the incidence of T1D) showed a clear restoration of IL-10 signaling.
Overall, these data reveal a novel immune defect that, if properly targeted could enhance the efficacy of immunomodulatory strategies to control T1D.
Critical role for OX40 signaling in Thymic and Peripheral Treg Expansion
Authors: Kumar Prabhakaran , Bhattacharya Palash , Epstein Alan L , Prabhakar Bellur S 
Published: January 2023

Abstract
Regulatory T-cells (Treg) play a pivotal role in suppressing self-reactive effector T-cells (Teff) and help maintain the critical balance between self-tolerance and autoimmunity. Restoration of homeostatic balance between Teff/Treg cells has been shown to ameliorate many autoimmune diseases including type-1 diabetes. Recently, we have reported a novel strategy for the selective expansion of Tregs using OX40L (a TNF-superfamily ligand) and Jagged (JAG)-1 (a Notch family ligand) treatment independent of canonical TCR-signaling, but mediated through specific interaction between OX40L-OX40 and JAG1-Notch3 preferentially expressed on Tregs. OX40L-JAG1 treatment of NOD mice with soluble OX40L and JAG1 increased proliferation of peripheral Tregs and delayed the onset of diabetes. In the present study, we show that OX40L treatment significantly increased Tregs in the thymus by inducing proliferation of thymic Tregs independent of TCR-stimulation upon addition of exogenous IL-2. OX40−/− mice had reduced numbers of thymic Tregs compared to wild type (WT) controls. The reduction in thymic Treg numbers likely due to impaired ability of proliferation in response to OX40L. However, we did not observe any change in IL-2 sensitivity of thymocytes in OX40−/− mice. Mechanistic studies suggested that OX40L-IL-2 induced thymic Treg proliferation was mediated through NF-kB and AKT-mTOR-S6 signaling. Further, phenotypic characterization studies revealed a significant decrease in TIGIT+Treg population, often associated with Treg activation, in both thymus and spleen of OX40−/− mice compared to WT controls. Taken together, these results suggest a critical role for OX40L/OX40 signaling in the development as well as function of Tregs.
Treg mediated immune system homeostasis requires NKAP association with HDAC3
Authors: Dash Barsha , Arocha Sinibaldo Romero , Chung Ji Young , Shapiro Virginia S. 
Published: January 2023

Abstract
NKAP is a transcriptional regulator essential for conventional T cell maturation. It does not have any previously defined DNA binding domains and is thought to interact with HDAC3 to exert its functions. The deletion of NKAP at the double positive stage (DP) in T cell development using the CD4-cre NKAP conditional knockout (cKO) mouse model renders thymocytes unable to incorporate α2,8-linked sialic acids and upregulate the complement inhibitory protein CD55, leading to rapid elimination of RTEs by complement. Here, we interrogate the importance of NKAP in Tregs. To address this, we created the Foxp3-YFP-cre NKAP cKO mouse model to delete NKAP only in the Treg lineage. Loss of NKAP in Tregs results in their disappearance, culminating in systemic autoimmunity, similar to the “scurfy” phenotype of Foxp3 mutant mice. Mice with Tregs lacking NKAP have increased conventional T cell proliferation, lymphocytic infiltration into various organs, and crusty skin on tail and ears, which necessitate euthanasia by three weeks. Preliminary results indicate that the disappearance of Tregs is a result of increased complement deposition. Transgenic expression of wildtype NKAP in a cre-inducible manner in cKO mice ameliorates the lymphoproliferative disease by restoring normal Treg numbers, and the mice are healthy. Interestingly, transgenic expression of a mutant version of NKAP that has lost its ability to bind HDAC3 is unable to prevent autoimmunity. Previous studies have demonstrated that HDAC3 is important for the generation and function of Tregs. Our results indicate that NKAP’s binding with HDAC3 is important for its role in Treg mediated immune system homeostasis.
Indole-3-carbinol ameliorates murine colitis symptoms through alterations in gut microbial composition and metabolomic pathways, particularly through decreasing disease-associated Bacteroides acidifaciens species.
Authors: Busbee Philip Brandon , Nagarkatti Mitzi , Nagarkatti Prakash 
Published: January 2023

Abstract
Colitis is an autoimmune disease characterized by acute or chronic inflammation of the large intestine. Currently there is no cure for patients suffering from colitis, and most treatments involve the use of immunosuppressive drugs that can have adverse side-effects or increased toxicity. In the current study, we show that indole-3-carbinol (I3C), a naturally-occurring plant product found in a number of cruciferous vegetables, was able to ameliorates symptoms in two well-established murine colitis models. In particular, I3C was able to prevent weight loss, reverse colon shortening, as well as reduce accumulation of disease-associated infiltrating immune cells and inflammatory biomarkers, such as serum amyloid A. We performed 16S rRNA metagenomic sequencing to investigate alterations in the gut microbiome after induction of colitis by TNBS and treatment with I3C. 16S analysis of cecal flushes and validation by PCR revealed that TNBS-induced colitis leads to a significant increase in the species Bacteroides acidifaciens, whereas colitis mice treated with I3C had decreased levels of this species, comparative to naïve controls. In addition, I3C was able to modulate gut microbial metabolites by way of altering short chain fatty acid (SFCA) production during disease induction. Lastly, transfer of disease and treated fecal material in antibiotic-treated disease mice confirmed I3C-mediated alterations in the gut microbial environment contributed to the ability of this natural compound to alleviate deleterious effects attributed to colitis. Collectively, these data suggest that I3C is able to ameliorate colitis by preventing pathogenic gut microbial dysbiosis and restoring gut microbiome composition to a more homeostatic state.
Persistence of gut microbiota may require repeated colonizations
Authors: Basu Srijani , Rao Aashima , Oswal Neelam , Bal Vineeta , Rath Satyajit , George Anna 
Published: January 2023

Abstract
Reports indicate that, variously, 10–50% of bacteria in the gut are coated with IgA and that bacterial diversity correlates with IgA amounts. In support of these observations, it was recently shown that there is an overall reduction in bacterial diversity in Rag1−/− mice. In extension to these findings, we report that taxa that are severely depleted in Rag1−/− mice include Proteobacteria and SFB, which are IgA-coated in wild-type (WT) mice. We reasoned that IgA might be required for these taxa to take up residence in the gut. Further, since germ-free SCID mice can be stably colonized with SFB, we explored the possibility that retention of SFBs may require continuous exposure to the organisms. We tested this by co-housing Rag1−/− mice with WT mice and found that by day 5, Rag1−/− mice had acquired both Proteobacteria and SFB. In addition, when F2 littermates obtained from WT x Rag1−/− crosses were compared for microbial diversity, both were present in the Rag1−/− pups. These data raise the possibility that mice are being colonized continuously. We also report that members of Proteobacteria separate equally into IgA-bound and IgA-unbound fraction, raising the possibility that the IgA-unbound fraction may represent new colonizers. Finally, in agreement with earlier reports, which showed that transfer of IgA-coated bacteria increases the susceptibility to DSS-colitis in germ-free mice, we find that Rag1−/− mice, which lack coated bacteria, are more resistant to DSS-colitis.
Evaluating the Therapeutic Potential of Transplantation of Neural Precursor Cells for Treating the Autoimmune Disease Multiple Sclerosis
Authors: McIntyre Laura Lynn , Plaisted Warren , Coleman Ronald , Loring Jeanne , Lane Thomas , Walsh Craig M 
Published: January 2023

Abstract
Multiple Sclerosis is a chronic, autoimmune disease for which there is currently no cure. Previous studies suggest transplantation of neural precursor cells (NPCs) is a promising therapeutic strategy to treat neurological disorders. Using two mouse models of MS, experimental autoimmune encephalomyelitis (EAE) and murine hepatitis virus (MHV), we have observed remyelination and decreased neuroinflammation when mice received an intra-spinal transplant of syngeneic mouse GFP-NPCs. This recovery was due to replacement of damaged cells and had little effect upon immune responses. In contrast, transplantation of xenogeneic human embryonic stem cell (hESC) derived NPCs (hNPCs) or induced pluripotent stem cell (iPSC) derived NPCs (hiNPCs) modulates the host immune response. Mice receiving intra-spinal transplants of human NPCs displayed less demyelination, decreased neuroinflammation, and an increase in T regulatory cells (Tregs). Recovery was not a result of cell replacement by hNPCs because transplanted cells underwent rapid xenograft rejection. Importantly, ablation of Tregs abrogated clinical and histopathological improvement mediated by hNPC transplantation. Furthermore, hNPCs promote the induction of naïve T cells into Tregs in co-cultures in vitro. However, the mechanisms and factors that propagate Treg induction and function resulting in subsequent endogenous remyelination remain undiscovered. We hypothesize rejection of NPCs plays a role in generation of Tregs in vitro and in vivo. Future experiments will focus on elucidating the factors from hNPCs that are responsible for Treg differentiation and evaluate the ability of syngeneic, allogeneic, and xenogeneic NPCs to generate Tregs.
CGEN-15001: a Novel B7-like regulator of immune homeostasis and inducer of Ag-specific tolerance
Authors: Hecht Iris , Rotman Galit , Chiang Ming-Yi , Neria Eyal , Miller Stephen D , Podojil Joseph R 
Published: January 2023

Abstract
B7 proteins play critical immunomodulatory roles and provide attractive targets for development of novel therapies for cancer and autoimmunity, both of which involve improper immune tolerance. A major medical need in autoimmunity is restoration of immune tolerance to self-antigens.
CGEN-15001, an Fc fusion protein of a novel B7-like protein that we identified, regulates immune homeostasis by inhibiting Th1/Th17 responses while enhancing Th2 and anti-inflammatory cytokines such as IL-10, and promoting iTreg differentiation. This was observed in vitro using murine cells and in PBMCs of healthy donors and MS patients, as well as in vivo in R-EAE model and in HY transplantation model. Short-term administration of CGEN-15001 in R-EAE model of MS and in NOD model of T1D resulted in durable therapeutic effects which lasted long after cessation of treatment, suggestive of restoration of immune tolerance. Treg blockade with anti-IL-10 or anti-TGFβ, and transient Treg neutralization with anti-CD25 abolished these therapeutic effects. Importantly, transferring CD4+ T cells from CGEN-15001-treated mice to naïve recipients protected them from R-EAE induction in Ag-specific manner, demonstrating induction of Ag-specific tolerance. In contrast, tolerance transfer was not achieved following CTLA4-Ig treatment in spite of the remission it induced in the donor mice.
In summary, CGEN-15001 has a unique mode of action, combining immunomodulation and regulation of immune homeostasis, as well as re-establishment of Ag-specific tolerance via enhancing Treg differentiation, leading to durable disease amelioration. These findings support the potential of CGEN-15001 to provide a promising therapeutic approach across autoimmune diseases.
Human gut-derived commensal Prevotella histicola suppress experimental autoimmune encephalomyelitis in humanized mice
Authors: Shahi Shailesh K , Freedman Samantha , Luckey David , Karau Melissa , Marietta Eric , Choung Rok-Seon , Gibson-Corley Katherine , Patel Robin , Rodriguez Moses , David Chella S , Taneja Veena , Murray Joseph A , Mangalam Ashutosh K 
Published: January 2023

Abstract
Our recent multiple sclerosis (MS) microbiome study indicates an important role of gut microbiota in pathogenesis of MS, an autoimmune disease of central nervous system. Gut microbiota help in maintaining immune-homeostasis by regulating balance between CD4+CD25+FoxP3+ regulatory T cells (Tregs) and pro-inflammatory Th1/Th17 cells. A shift of balance towards Th1/Th17 cells leading to inflammation and demyelination in central nervous system (CNS), is suggested to be responsible of disease initiation and/or relapses in MS. Therefore, gut commensals capable of restoring the microbiome to a healthy state could provide novel therapeutic options for treating autoimmune diseases including MS. Here, we report identification of human gut-derived commensal bacteria, Prevotella histicola (P. histicola), which can suppress an autoimmune disease in HLA class-II transgenic model of experimental autoimmune encephalomyelitis (EAE), an experimental model of MS. P. histicola suppresses disease through modulation of systemic immune response. P. histicola challenge led to a decrease in pro-inflammatory Th1 (IFNγ) and Th17 (IL17) cytokines, and increase in the frequencies of CD4+FoxP3+ Tregs, tolerogenic dendritic cells and suppressive macrophages. We also observed that mice with EAE had a altered gut microbiota compared to naïve mice and treatment with P. histicola restored gut flora to a normal state which further support an important role of gut microbiota in EAE/MS. Our study provides compelling evidence that administration of gut commensals may regulate a systemic immune response and have a possible role in the treatment of autoimmune diseases.
A unique tolerizing dendritic cell phenotype induced by the synthetic triterpenoid CDDO-DFPA is protective against EAE
Authors: Wei Hsi-Ju , Pareek Tej K , Liu Qi , Letterio John J. 
Published: January 2023

Abstract
Dendritic cells (DCs) have emerged as relevant targets for the treatment of multiple sclerosis (MS) and other autoimmune disorders. Strategies that exploit their tolerogenic potential are now under clinical investigation. However, the essential pathways and optimal methods for the induction of tolerogenic DCs (TolDCs) remain intense areas of research. Triterpenoids are a class of small molecules with potent immunomodulatory activity linked to activation of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) target genes, and that suppress the manifestations of experimental autoimmune encephalomyelitis (EAE). Here we reveal DCs as a principal target of the immune modulating activity of triterpenoids in the context of EAE. Exposure of bone marrow-derived murine DCs to the triterpenoid 2-cyano-3, 12-dioxooleana-1, 9(11)-dien-28-oic acid-difluoro-propyl-amide (CDDO-DFPA) results in the induction of heme oxygenase-1 (HO-1), transforming growth factor-beta (TGF-β) and interleukin-10 (IL-10), as well as the repression of NF-kB, endothelin-1 (EDN-1) and of the pro-inflammatory cytokines IL-6, IL-12 and TNF-α. CDDO-DFPA exposed DCs retained expression of cell surface ligands and their capacity for antigen uptake but were impaired in their induction of Th1 and Th17 cells in vitro and in vivo. TGF-β was identified as the factor mediating suppression of T cell proliferation by CDDO-DFPA pretreated DCs in vitro, and MOG (35–55) pulsed CDDO-DFPA-pretreated DCs failed to passively induce EAE in vivo. These findings demonstrate the potential therapeutic utility of CDDO-DFPA in the treatment and prevention of autoimmune disorders, and more broadly the capacity of triterpenoids to induce tolerance via modulation of the DC phenotype.
CpG type-A induction of an early protective environment in experimental multiple sclerosis
Authors: Manni Giorgia , Gargaro Marco , Crooks James , Pirro Matteo , Scalisi Giulia , Turco Antonella , Romani Rita , Matino Davide , Rostami Abdolmohamad , Puccetti Paolo , Gran Bruno , Fallarino Francesca 
Published: January 2023

Abstract
Experimental autoimmune encephalomyelitis (EAE) is an inflammatory, demyelinating disease of the CNS that mimics human multiple sclerosis (MS), and it is thought to be driven by Th1 and Th17 myelin-reactive cells. Although adaptive immununity is clearly pivotal in the pathogenesis of EAE – with an essential role of CD4+ T cells – little is known of early, innate responses in this experimental setting. CpG-rich oligodeoxynucleotides (ODNs), typically found in microbial genomes, are potent activators of TLR9 in plasmacytoid dendritic cells (pDCs). In this study, we compared the effects of two types of CpG, namely, type A and type B, on EAE. We found that treatment with CpG type-A ODN (CpG-A) – known to induce high amounts of IFN-α in pDCs – significantly reduced disease severity in EAE, relative to controls (12.63 ± 1.86 vs. 23.49 ± 1.46, respectively; p = 0.001). Treatment also delayed onset of neurological deficits and reduced spinal cord demyelination, while increasing the percentage of splenic regulatory (Foxp3+CD4+) T cells. CpG-A likewise reduced the levels of IL-17 and IFN-γ in the CNS. Mechanistic insight into those events showed that CpG-A promoted a regulatory phenotype in pDCs. Moreover, adoptive transfer of pDCs isolated from CpG-A–treated mice inhibited CNS inflammation and induced disease remission in acute-phase EAE. Our data thus identify a link between TLR9 activation by specific ligands and the induction of tolerance via innate immunity mechanisms.
Selective inhibition of matrix metalloproteinase-9 in CD4+ T-cells reduces clinical severity in a murine model of Multiple Sclerosis.
Authors: Onwuha-Ekpete Lillian C. , Tokmina-Roszyk Dorota , Fields Gregg B. 
Published: January 2023

Abstract
Matrix metalloproteinases (MMPs) are a family of proteolytic enzymes that mediate the degradation of extracellular matrix components. Their functions are essential for normal physiological processes such as leukocyte trafficking, but their dysregulation is associated with various pathologies including Multiple Sclerosis (MS). During MS, CD4+ T-cells activated in the periphery penetrate the blood-brain barrier (BBB), recruit immune cells, initiate destruction of the myelin sheath, and cause axonal loss. Experimental Autoimmune Encephalomyelitis (EAE) is a well-established murine model of MS. In EAE, MMP-9 is required for penetration of the BBB and generation of auto-antigens. Recent studies have demonstrated that MMP-9 contributes to normal intracellular function of various cell types including antigen activated T-cells; however, the intracellular role of MMP-9 in immune cell activation during EAE pathogenesis is not known. In our studies, we demonstrate that the MMP-9 is important for homeostatic maintenance as well as a robust antigenic stimulation. Upon activation, CD4+ T-cells treated with an MMP-9 inhibitor demonstrate a reduced ability to enter cell cycle, proliferate, and produce cytokines. In addition, RNA-seq analysis highlight key proteins associated with the T-cell receptor signaling pathway that are impacted. Furthermore, treatment of EAE mice resulted in reduced clinical severity. This reduction is associated with a treatment regimen that starts on Day 7 as opposed to Day 0, suggesting that CD4+ T cells are more sensitive to the impact of MMP-9 inhibition compared to other immune cells. These results emphasize the importance of MMP-9 as a therapeutic target in CD4+ T-cell mediated autoimmune diseases.