bluuebunny/crossref_metadata_2025_split huggingface dataset:
Helios plays a critical role in the effective differentiation of naive CD4+ T cells in vivo.
Authors: Skadow Mathias , Shevach Ethan M , Thornton Angela M 
Published: January 2023

Abstract
The transcription factor Helios is required for the maintenance of the suppressive phenotype of Foxp3+ regulatory T cells (Tregs) as evidenced by the spontaneous autoimmune activation that develops in mice with a Foxp3-specific Helios deficiency. Helios is also upregulated in a subset of activated CD4+Foxp3−T conventional (Tconv) cells, but its role in Tconv cells remains unknown. Mice with a CD4-Cre driven Helios deletion do not exhibit autoimmunity despite the defect in the suppressor function of their Treg population, pointing to a requisite function of Helios in the activation of Tconv cells in response to antigen. We examined the capacity of Helios-deficient, naïve Tconv cells to respond to their cognate antigen in vivo and found that Helios was not required for proliferation, differentiation into helper subsets, or the production of effector cytokines. Unexpectedly, we observed that Helios deficiency increased the susceptibility of naïve T cells to differentiate into Tregs under inflammatory conditions. Additionally, we found that Helios is necessary for the reactivation of memory T cells as Helios-deficient T cells failed to proliferate upon secondary challenge with antigen. Together, these findings suggest that increased Treg differentiation in the periphery and defective memory T cell reactivation in mice with a CD4-Cre driven Helios deletion may prevent the development of autoimmunity normally associated with Helios-deficient Tregs.
Novel microRNAs in the pathogenesis of rheumatoid arthritis
Authors: Singh Ram Pyare , Hahn Bevra H 
Published: January 2023

Abstract
Rheumatoid arthritis (RA) is a systemic inflammatory autoimmune disease with progressive joint destruction, lifelong disability, functional deterioration, and high mortality. The major effector cells in RA are T cells and synovial fibroblasts. Defects in T cells and synovial fibroblasts lead to activation of proinflammatory cytokines, which induce Th1 and Th17 cells and chronic inflammation. Recent studies provide further evidence of dysregulation of candidate microRNAs in inflammation and autoimmunity. In our preliminary studies we have found dysregulated candidate microRNA (miRNA21, miR25 miR95, miR124a, miR146a and miR186) expression in RA patients compared to healthy controls. Furthermore proinflammatory cytokines such as IL-6, IL-12, IL-17 and IL-21 are significantly increased in RA patients compared to healthy controls, and expression of these cytokines positively correlates with the expression of candidate microRNAs such as miR21 and negatively correlates with the expression of miR146a. Furthermore we found that miR21 and miR124a positively correlate, and miR146a negatively correlates, with DAS28 score in RA patients. Based on these preliminary data, we hypothesize that dysregulated microRNAs play an important role in RA pathogenesis. This study has translational potential and may identify novel therapeutic targets in patients with RA.
SOCS1-KIR peptide inhibition of lupus pathology is correlated to enhanced PD1/PDL1 expression
Authors: Collins Teresa D. , Mishra Shiwangi , Lam Brandon Krishna , Mohamed Zaynab Sidi , Veal Antia E. , Johnson Howard M. , Larkin Joseph 
Published: January 2023

Abstract
Lupus progression is driven by the accumulation of auto-inflammatory T cells producing cytokines such as interferon-gamma (IFN-γ). As such, the enhancement of co-inhibitory signaling pathways or retardation of inflammatory programming in T cells are potential strategies to ameliorate lupus pathologies. Notably, Suppressor of Cytokine Signaling-1 (SOCS-1) is a critical regulator of the Jak/STAT pathway, and pro-inflammatory cytokines associated with lupus. We have previously shown that a peptide mimicking SOCS1 signaling (SOCS1-KIR) inhibited IFN-γ signaling and auto-inflammatory disease progression. In this study, we test the hypothesis that SOCS1-KIR administration will inhibit lupus pathology in MRLlpr/lpr mice. A 3x/week administration of SOCS1-KIR mediated a statistically significant reduction in spontaneous skin lesions and the accumulation IFN-γ producing memory cells within the peripheral blood, spleen, and lymph nodes. Notably, SOCS1-KIR mediated decreases in lympho-accumulation were correlated to increased levels of the co-inhibitory molecules, PD1 and PD-L1 in vivo. In vitro interrogation revealed that SOCS1-KIR, but not a control peptide, mediated the upregulation of PD1 on CD8+ and CD4+ T lymphocytes in 5 days of culture. Moreover, SOCS1-KIR facilitated PDL1 surface expression on antigen presenting cells. Together, these data show that SOCS1-KIR treatment was effective in mitigating auto-inflammatory T cell accumulation and effector functions. Moreover, these studies suggest an interplay between SOCS1 function and PD1/PD-L1 signal regulation.
Mesenchymal stem cells ameliorate lupus symptoms in MRL/lpr mice by inhibiting T cell functions in a CCL2 dependent manner
Authors: Kim Ki Hun , Lee Hong Kyung , Lee Jae Hee , Kim Ji Sung , Choi Jeong Eun , Ji A Young , Hong Jin Tae , Kim Youngsoo , Han Sang-Bae 
Published: January 2023

Abstract
Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by the emergence of autoreactive lymphocytes, autoantibody production, and deposition of immune complexes in various tissues. Mesenchymal stem cells (MSCs) ameliorate SLE by inhibiting T cell functions, but the underlying mechanisms remain incompletely understood. Human MSCs increased the survival rates of lupus-prone MRL/lpr mice by inhibiting cytokine expression and kidney infiltration of T cells. In cellular assays, allogeneic MSCs inhibited the proliferation and the cytokine production of MRL/lpr-derived T cells. Using time-lapse imaging, we examined how MRL/lpr-derived T cells gather information from MSCs at the single-cell level. Wild type MSCs demonstrated induction of T cell migration, and long-term contact duration than CCL2-knockdowed/knockout MSCs. MSC-driven CCL2 increased the expression of vascular cell adhesion molecule-1 expression in MRL/lpr-derived T cells. Taken together, our study helps to understand how MSCs inhibit autoreactive T cell functions by using CCL2 and ultimately how MSCs ameliorate symptoms in lupus-prone MRL/lpr mice.
LXR and RORG modulate bi-directional, sumoylation-dependent pathways in chronic autoimmune diseases
Authors: Chang Mi Ra , Strutzenberg Timothy , Griffin Patrick Robert 
Published: January 2023

Abstract
The nuclear receptor RORG (RAR-related orphan receptor gamma; NR1F3) plays an essential role in the development of T helper cells leading to the production of interleukin-17. Previously, we reported that the potent and selective RORG inverse agonist SR2211 was effective at repressing RORG activity in cultured cells and also demonstrated robust efficacy in a murine model of arthritis, the collagen induced arthritis (CIA) model. Lead optimization of the SR2211 chemical scaffold lead to the identification of compounds that maintain potent RORG-specific inverse agonism while exhibiting modest LXR activation. One such compound, SR1903, demonstrated improved efficacy in the CIA model with significantly improved therapeutic index. Proteogenomic analysis revealed that SR1903 increased expression of SENP3 (SUMO1/Sentrin/SMT3 specific peptidase 3) resulting in SUMOylation-dependent, opposing modulation of RORG and LXR activities upon inflammatory stimulation of T cells. Ongoing mutational studies and receptor trafficking analysis will provide additional mechanistic insight into this novel inflammatory process particulary in the context of NCoR tethering to promoters of RORG and LXR target genes.
V1V2 multivalent scaffolds induce focused antibody responses with functional activity, prolonged durability, and modest neutralization potency
Authors: Hessell Ann Jones , Jiang Xunqing , Totrov Max , Powell Rebecca , Hioe Catarina , Haigwood Nancy L. , Kong Xiang-Peng , Zolla-Pazner Susan 
Published: January 2023

Abstract
The V1V2 region of HIV-1 gp120 is vulnerable to a group of broadly neutralizing monoclonal antibodies (bnMAbs), and RV144 vaccinees developed strongly binding Abs to this region that correlated with a reduced risk of infection. This region of Env is now recognized as an important vaccine target, notwithstanding its relatively poorly immunogenic epitopes. We hypothesized that presenting V1V2 in multivalent scaffolds could improve immunogenicity and structurally constraining the epitopes could induce a more focused immune response in animal models. We designed of a panel of immunogens engrafting the V1V2 domain into trimeric and pentameric scaffolds. Here, we report results of immunogenicity studies in nonhuman primates (NHP) with 2 different V1V2 trimeric scaffolds. Our experimental approach in NHP consisted of 3 DNA and protein co-immunizations and a single protein boost. The DNA components consisted of 50μg of ZM109 gp120 plasmid delivered by gene gun with a simultaneous intramuscular injection of 100 μg of V1V2 scaffold protein immunogens. NHP immune responses were specific for V1V2 conformational epitopes with cross-reactive binding to heterologous gp120s and were functionally active in phagocytosis assays. Notably, V1V2 binding Ab responses were detectable 2 years after immunizations ceased. Neutralizing Abs developed in vaccinated NHP to Tier 1A and 1B, Clade B and Clade C viruses. The V1V2 structurally constrained scaffolds show promise as novel and highly effective at inducing functional antibody responses specifically targeted to the epitopes presented. Our results advance pre-clinical data in support of developing V1V2 vaccine candidates despite the structural complexity of the region.
Funding: P01AI100151-03
Antibody epitopes identified in critical regions of dengue virus nonstructural 1 protein in mouse vaccination and natural human infections
Authors: Hertz Tomer , Beatty Robert P , MacMillen Zachary , Killingbeck Sarah S , Wang Chunling , Harris Eva 
Published: January 2023

Abstract
A major challenge in dengue vaccine development is that cross-reactive anti-DENV antibodies (Abs) can be protective or potentially enhance disease via antibody-dependent enhancement (ADE). We recently showed that immunization with adjuvanted recombinant NS1 from all four DENV serotypes protects against DENV2 challenge in a mouse model of lethal vascular leak syndrome. Conversely, we found that DENV NS1 by itself triggers endothelial permeability in vitro and vascular leak in vivo. Here, we evaluated survival to lethal DENV challenge in mice immunized with (1) NS1+alum; (2) NS1+Monophosphoryl Lipid A and AddaVax (MA); (3) NS1+Sigma adjuvant system and CpG DNA (SCpG); (4) ovalbumin+adjuvant (OVA); or (5) a sublethal dose of DENV2 strain PLO46.NS1. OVA or NS1+alum immunized mice were not protected, whereas immunization with NS1+MA or NS1+SCpG or DENV2-PL046 resulted in 100% survival. We characterized Ab responses to NS1 from DENV1-3 using an antigen microarray tiled with 20-mer peptides overlapping by 15 amino acids and identified 5 regions with significant levels of antibody reactivity in the NS1+MA group. We also profiled Ab responses to NS1 in humans naturally infected with DENV-2 or -3 in longitudinal serum samples from Nicaragua. One region in the NS1 “wing” domain was immunodominant in both mouse and human studies, and two regions were identified only in NS1-immunized mice; thus, vaccination can generate Abs to regions that are not targeted in natural infection and could provide additional protection against a lethal DENV infection. Overall, we identified several immunodominant regions, which were in functionally important locations on the DENV NS1 protein and are potential correlates of protection.
Intradermal Delivery of INO-4201 Drives Robust Ebola Glycoprotein Specific Humoral and Cellular Immune Responses in Healthy Volunteers in an Open Label Phase I Trial
Authors: Kraynyak Kimberly Ann , Amante Dinah , Tebas Pablo , Knoblock Dawson , Sylvester Albert J , Morrow Matthew P , Prostak Naseem , Liu Li , Sakata Lindsay , Cheung Jocelyn , Desfor Shane , Patel Ami , Dallas Michael , Yan Jian , Khan Amir , Boyer Jean D , White Scott , Maslow Joel , Humeau Laurent , Sardesai Niranjan , Weiner David , Bagarazzi Mark 
Published: January 2023

Abstract
The most recent Ebola outbreak in West Africa resulted in over 28,000 suspected cases of infection and over 11,000 deaths. As no specific immune correlate has been associated with protection against Ebola to date, the development of a vaccine that generates robust humoral and cellular immune responses may be the best approach to achieve full protection. INO-4201 is a plasmid-based prophylactic vaccine targeting Zaire Ebola glycoprotein (GP), designed to prevent Ebola infection. INO-4201 encodes a consensus antigen that encompasses genetic variability from previous outbreak strains to broaden immune coverage for divergent Ebola virus variants. Intradermal (ID) administration of a 2 or 3-dose regimen of INO-4201 followed by in vivo electroporation with the CELLECTRA® device was well tolerated in 140 healthy volunteers with no related Grade 3 or Grade 4 SAEs reported. INO-4201 induced robust Ebola GP-specific antibody and T cell responses in the healthy volunteers. The majority of patients seroconverted, as gauged by binding ELISA after only 2 doses of INO-4201. EBOV GP specific T cell response were assessed by Interferon gamma (IFNγ) ELISpot revealing a mean peak response magnitude of 295 SFU per 106 PBMCs. Intracellular cytokine staining indicated that immunization with INO-4201 drove statistically significant increases in the production of IFNγ or Tumor Necrosis Factor alpha in both the CD8+ T cell compartment (p=0.001) and CD4+ T cell compartment (p=0.004). ID administration of INO-4201 using the CELLECTRA® device was well tolerated and immunogenic as assessed by both humoral and cellular EBOV GP-specific immunoassays supporting INO-4201 as a strong candidate for further clinical development of a prophylactic Ebola vaccine.
Transcription of immune genes at the fetomaternal interface during pregnancy in a model marsupial, Monodelphis domestica.
Authors: Hansen Victoria L , Miller Robert D 
Published: January 2023

Abstract
The evolutionary challenge of nourishing an allogeneic conceptus in the presence of an adaptive immune system has intrigued immunologists since Sir Peter Medawar brought attention to the “fetal allograft problem” in the 1950s. Though much has been learned in reproductive immunology, it has largely been limited to eutherian mammals such as humans, mice, and mammalian livestock. Therians are the lineage of mammals that include both eutherians, or “placentals”, and marsupials. Though eutherians and marsupials diverged approximately 148 million years ago, the two lineages share a common viviparous ancestor. Therefore marsupials and eutherians likely share immunological traits during pregnancy. Previous RNA-Seq studies demonstrated increased transcription of immune genes in late, terminal pregnancy. However since the RNA-Seq data only represented one pregnancy time point, less than 24 hours until birth, it was unclear whether immune gene transcription should be attributed to pregnancy, implantation, or parturition. We expanded time points to target the last 144 hours of pregnancy during which both implantation and parturition occur in Monodelphis domestica. We examined the transcription of cytokines as well as complement and their regulators at the fetomaternal interface in pregnant opossums. We found a significant increase in transcription of cytokines in the last 24 hours of pregnancy and comparatively little transcription of cytokines at the time of implantation. There was also little transcription of some complement components throughout pregnancy, particularly those in the upstream cascade. Some downstream complement components trended toward increased transcription in the last 48 hours of pregnancy.
Interaction of γδ TCR with the WC1 hybrid co-receptor/pathogen recognition receptor in cattle.
Authors: Gillespie Alexandria , Connelley Timothy , Telfer Janice C , Baldwin Cynthia L 
Published: January 2023

Abstract
Ruminants have a larger proportion of γδ T lymphocytes in blood compared to mice and humans. These lymphocytes are first responders to pathogens such as Leptospira and Mycobacterium. Bovine γδ T cells that respond to these pathogens express members of a unique γδ T-cell specific molecular family WC1 that are hybrid pattern recognition receptors and signaling co-receptors. Only γδ T cells that express WC1 molecules that bind to the pathogens selectively respond by proliferation and cytokine production. WC1 molecules have also been shown to augment signaling when co-crosslinked with the TCR but cannot signal on their own. Silencing WC1 through shRNA results in inhibition of the response to leptospira. Together these data indicate that WC1 is crucial for activation of the cells and we wished to further understand how the TCR interacts with WC1. The TCR is transcribed from a recombination of variable, joining, and diversity genes resulting in hundreds to millions of different possible sequences while the WC1 family has only 137 different pathogen-binding SRCR domains coded for by 13 genes. Yet only γδ T cells that express particular WC1 family members respond to leptospira suggesting it has primacy. We hypothesize that WC1 molecules co-localize with the TCR following binding of the pathogen. To test this hypothesis we used Imaging flow cytometry. Using FRET analysis we are able to determine that not only are the TCR and WC1 co-localized in the synapse following activation but they also are interacting closely within 9nm of each other. To evaluate the role of the TCR in dictating specificity of the response we are using next generation sequencing of transcripts coding for the TCR gamma and delta chains in leptospira-responsive cells.
Comparison genomics of two closely related isolates of Clostridium perfringens full genome sequences reveals regions of genome plasticity with prevention potential
Authors: Li Charles Z , Yan Xianghe , Lillehoj Hyun S. 
Published: January 2023

Abstract
The spore-forming anaerobic Clostridium perfringens (CP) is the primary etiological agent of necrotic enteritis (NE) disease, one of priority enteric diseases in chickens which is responsible for annual losses of $6 billion in the US poultry industry. Our long term goal is to develop a recombinant vaccine against NE as an antibiotic alternative. Because the design of effective vaccines requires a thorough understanding of the pathogen’s entire genome and their functions, we sequenced the genomes of two closely related Type A CP strains: Del1 and CP15, isolated from NE-afflicted chicken farms. Del1 is very virulent, while CP15 produced very mucoid supernatant in its growth medium culture. PacBio and Illumina sequencing technologies were used to generate accurate de novo and hybrid genome assemblies. In this study, these two assembled full genomes are deposited into NCBI GenBank, annotated and analyzed. Del1 has a circular genome of 3.55 M base pairs (bp) long and four plasmids (82326, 69601, 49550, and 49456 bp) with a total of 3361 predicted open reading frames. CP15 has a genome of 3.34 M bp long and four plasmids (14755, 3843, 3202 and 2421 bp) with a total of 2997 predicted CDS. The sequenced data revealed that Del1 contains a pore-forming toxin netB encoded within one of highly conserved NE-associated loci. In contrast, CP15 did not contain netB gene. Sequenced data also showed that Del1 has a unique ribosomal protection protein which protects ribosomes from the translation inhibition of tetracycline (YP_001967743). These results provide important insight into the pathogenesis of CP in avian NE and novel information on potential targets of toxins and virulence factors that will facilitate the vaccine design.
Missense variant in XYZ results in hyperactivation of mTOR signaling pathway and increased T-cell senescence
Authors: Raquer Hayley M , Fritz Jill , Lenardo Michael 
Published: January 2023

Abstract
Phosphatidylinositol-4-phosphate 5-kinase I (XYZ) is a member of the class I PIP5K family that is responsible for the phosphorylation of phosphatidylinositol 4-phosphate (PIP) to produce phosphatidylinositol 4,5-biphosphate (PIP2). PIP2 is an important intermediate in the PI3K signaling pathway and is phosphorylated by PI3K to create phosphatidylinositol 3, 4, 5-triphosphate (PIP3), which is an important signaling molecule in TCR activation. Through whole exome sequencing, we have recently identified a 14-year old female Turkish patient with a homozygous missense variant in the activation loop of XYZ. The patient presents with lymphadenopathy, hemolytic anemia, low IgA, no IgE, positive antinuclear antibodies, and reactive airway disease. She has low naïve T-cells, increased CD45RA+ T-effector memory (TEMRA) cells, and increased CD57, a marker of T-cell senescence, on CD8+ T-cells. Patient T-cell blasts show increased phosphorylation of S6 levels upon TCR stimulation. Further, overexpression of mutant XYZ in T-cells resulted in increased phosphorylation of S6 at baseline compared to overexpression of wild type XYZ. Overall, these results suggest that the XYZ variant leads to hyperactivation of the mTOR signaling pathway, which may contribute to T-cell senescence and disease.
This research was supported [in part] by the Intramural Research Program of the NIH, NIAID
Defective activation of IL2-inducible T cell kinase (ITK) in XMEN disease
Authors: Kanellopoulou Chrysi , George Alex B , Masutani Evan , Jiang Ping , Ravell Juan C , Chaigne-Delalande Benjamin , Lenardo Michael 
Published: January 2023

Abstract
We have previously described a primary immunodeficiency due to mutations in the magnesium transporter MAGT1, named XMEN disease (X-linked Magnesium defect with Epstein-Barr infection and Neoplasia). Loss of MAGT1 results in impaired T cell receptor signaling. Previous analyses suggested that proximal TCR signaling was unaffected in XMEN patients but PLCg1 phosphorylation was delayed. We have further characterized the TCR activation defect in MAGT1 deficient cells and found that the primary cause is the impaired activity of Interleukin-2 inducible T cell kinase (ITK). ITK is phosphorylated normally by LCK and recruited to immunological synapse but fails to phosphorylate downstream targets efficiently. A similar phenotype is apparent when cells from normal controls are activated in the absence of extracellular magnesium. A transient influx of magnesium is sufficient to restore ITK activity and PLCg1 phosphorylation in XMEN T cells. We are in the process of further characterizing the molecular underpinnings of ITK regulation by MAGT1.
Acknowledgements:
This research was supported by the Intramural Research Program of NIAID, NIH
Recruitment of calcineurin to the T cell receptor positively regulates T cell activation
Authors: Dutta Debjani , Barr Valarie A , Akpan Itoro , Mittelstadt Paul R , Singha Laishram Indira , Samelson Lawrence E , Ashwell Jonathan D 
Published: January 2023

Abstract
Calcineurin is a phosphatase whose primary targets in T cells are NFAT transcription factors, and its inhibition with cyclosporin A (CsA) or FK506 is a cornerstone of immunosuppressive therapies. Here we show that calcineurin is recruited to the T cell receptor signaling complex where it reverses the inhibitory phosphorylation of Lck on Ser-59 (LckS59). Loss of calcineurin activity impaired phosphorylation of ZAP-70Y493 and some downstream pathways in a manner consistent with signaling in cells expressing LckS59A (non-phosphorylatable) or LckS59E (phosphomimetic). Importantly, CsA inhibited activation-induced LFA-1-dependent and NFAT-independent adhesion of T cells to ICAM-1, with little effect on cells expressing mutant Lck. These results provide a new understanding of how widely-used immunosuppressive drugs interfere with essential processes in the immune response.