bluuebunny/crossref_metadata_2025_split huggingface dataset:
PD-1 and Tim-3 regulate the expansion of vaccine-induced tumor antigen-specific CD8+ T cells in patients with advanced melanoma (VAC3P.944)
Authors: Fourcade Julien , Sun Zhaojun , Pagliano Ornella , Chauvin Joe-Marc , Wang Hong , Sander Cindy , Janjic Bratislav , Tarhini Ahmad , Tawbi Hussein , Kirkwood John , Moschos Stergios , Guillaume Philippe , Luescher Immanuel , Krieg Arthur , Anderson Ana , Kuchroo Vijay , Zarour Hassane 
Published: January 2023

Abstract
Although melanoma vaccines stimulate tumor antigen (TA)-specific CD8+ T cells, objective clinical responses are rarely observed. To investigate this discrepancy, we have evaluated vaccine-induced CD8+ T cells for frequency, function and expression of the inhibitory receptors PD-1 and Tim-3 in patients with metastatic melanoma immunized with incomplete Freund’s adjuvant, CpG-oligodeoxynucleotide, and the HLA-A2-restricted analog peptide NY-ESO-1 157-165V either alone, or in combination with the pan-DR epitope NY-ESO-1 119-143. Both vaccines stimulated rapid TA-specific CD8+ T cell responses detected ex vivo, however, TA-specific CD8+ T cells produced more IFN-γ and exhibited higher lytic function upon immunization with MHC class I and class II epitopes. Notably, the vast majority of vaccine-induced CD8+ T cells upregulated PD-1 whereas a minority also upregulated Tim-3 and the levels of PD-1 and Tim-3 expression by vaccine-induced CD8+ T cells at the time of vaccine administration inversely correlated with their expansion in vivo. PD-1 and Tim-3 blockades further enhanced the expansion and cytokine production of vaccine-induced CD8+ T cells in vitro. Collectively, our findings support the use of PD-1 and Tim-3 blockades in addition to cancer vaccines to stimulate potent antitumor T cell responses and increase the likelihood of clinical responses in patients with advanced melanoma.
Endogenous anti-β-glucan antibodies, a potential predictive biomarker for the efficacy of soluble yeast β-1,3/1,6 glucan (Imprime PGG®) immunotherapy in cancer patients (VAC3P.947)
Authors: Antonysamy Mary , Bose Nandita , Chan Anissa , Ertelt Katie , Gorden Keith , Grossman William , Huhn Richard , Jonas Adria , Leonardo Steven , Lowe Jamie , Mattson Paulette , McMurray Diane , Nelson Mariana , Ottoson Nadine , Patchen Myra , Qiu Xiaohong , Rathman Blaine , Walsh Richard , Wurst Lindsay , Yokoyama Yumi 
Published: January 2023

Abstract
The innate immune response to Imprime PGG® (Imprime PGG) is being leveraged to develop a novel cancer immunotherapy in conjunction with anti-tumor monoclonal antibodies. Previous research has demonstrated the presence of endogenous anti-β-glucan antibodies (ABA) as a necessary prerequisite for the binding and functional activity of Imprime PGG in innate immune cells. In this study, healthy donors with varying levels of ABA were evaluated to determine the threshold of ABA above which binding and modulation of functions were observed. Donors who had ABA levels above the threshold showed Imprime PGG binding (&gt; 5%) to their neutrophils and monocytes with significant modulation of functions, including, a) activation of complement (C5a), b) increased surface expression of complement receptor 3, c) modulation of activation markers (CD62L), and d) production of selective chemokines (IL-8). The potential of the ABA level being a clinical biomarker was then evaluated in a non-small cell lung cancer trial by segregating patients into biomarker (BM) positive or negative populations based on the established ABA threshold. The BM positive patients showed a significantly increased objective response rate and marked survival benefit not seen in the BM negative patients. These results demonstrate a successful translation of biomarker discovery in healthy donors to clinical utility in cancer patients. ABA is a potential predictive biomarker for efficacy of Imprime PGG immunotherapy.
Regulation of Inflammatory Bowel Disorder by ST8Sia6
Authors: Crotts Sydney B , Antonetti Regina , Shapiro Michael J , Rajcula Matthew , Theodore Keith , Lee Hyun Se Kim , Shapiro Virginia 
Published: January 2023

Abstract
Inflammatory bowel disorders (IBD) including ulcerative colitis (UC) and Crohn’s disease (CD) affect between 1–3 million people in the United States with prevalence on the rise. Patients present with symptoms including diarrhea, abdominal cramps, and weight loss. Many factors are implicated in pathogenesis, including host immune response. Identification of molecules that regulate IBD is critical in understanding pathogenesis. ST8Sia6 is a sialic acid transferase that adds terminal a2,8 disialic acids to cell surface glycoproteins, and we have found that ST8Sia6 knockout (KO) mice exhibit increased spontaneous small bowel lamina propria CD4 TH1 polarization, increased inflammatory cytokine production, and decreased IgA class switching of Peyer’s patch B cells, indicative of inflammation. Additionally, adult ST8Sia6 KO mice have shortened small bowels, likely due to baseline inflammation. These mice do not exhibit obvious baseline symptoms, but ST8Sia6 KO mice exhibit increased weight loss and decreased survival when challenged with dextran sodium sulfate (DSS)-induced colitis, which was also enhanced when co-housed with wildtype (WT) mice and after antibiotic treatment. These DSS-challenged ST8Sia6 KO mice exhibit increased histological damage and immune infiltration of the gut as compared to WT controls. The accelerated DSS-colitis is also observed when ST8Sia6-deficient bone marrow is transplanted into WT recipients, indicating that the effect is mediated specifically by immune cells. This data demonstrates a role for ST8Sia6 in regulating the host immune response to inflammatory bowel disorders, and further elucidating this role will aid in developing a mechanistic understanding of IBD pathogenesis.
Supported by grants from NIH R01 CA243545
Phenotype of CD39/CD73 expressed on T cells in a mouse model of IPEX syndrome
Authors: Liu Yuying , Armbrister Shabba A , Okeugo Beanna , Daniel Rhea C , Rhoads J Marc 
Published: January 2023

Abstract
The combination of CD39 and CD73 degrade ATP to adenosine that shifts ATP-driven pro-inflammatory immune cell activity toward an anti-inflammatory state. This immunological switch is a major mechanism for regulatory T cells (Tregs) to control inflammation. However, in Treg-deficiency-induced autoimmune pathologies, exemplified by IPEX syndrome (immune dysregulation, polyendocrinopathy, enteropathy, with X-linked inheritance, as modeled by the scurfy (SF) mouse), the expression of these molecules on T cells is unknown. We analyzed homeostatic markers CD39 and CD73 on T cells in spleen and peripheral blood by flow cytometry in SF males and their sibling WT male mice at d21. Among Foxp3+ Tregs in WT mice, ~68% cells had CD39 and 85% cells had CD73 expression. In the spleens of SF mice, the % of CD39+ CD4+ T cells was higher than the % in WT mice, while no difference was observed in the CD73+ CD4+ T cells. In addition, the data showed ~70% of NonTregs expressed CD39, 2-fold higher than both % of CD73+ NonTregs in SF, and % of CD39+ NonTregs in WT. Only ~10% of these CD39+ and CD73+ NonTregs had the CD25 expression. The proportion of CD8+ T cells in splenocytes and blood of SF mice were significantly higher than those in WT mice. Amongst CD8+ T cells, the % of CD39+ T cells was significantly increased, conversely, the % of CD73+ T cells was significantly decreased in SF compared to WT mice. We conclude that normally, CD73 is a more highly expressed Treg surface marker than CD39; however, in Treg-deficiency, there is a higher expression by CD4+ T and CD8+ T cells of CD39 than CD73; and CD39 and CD73 expression may not be due to cell activation. This study provides data to aid further discovery of potential biomarkers and therapeutic targets in Treg deficiency diseases.
Supported by grants from NIH/NIAID (R03AI153725)
EGR2 deletion displays similar and differential effects on immunological development and function in autoinflammation-prone B6/lpr and normal B6 mice
Authors: Dai Rujuan , Wang Zhuang , Heid Bettina , Eden Kristin , Reilly Christopher M , Ahmed S Ansar 
Published: January 2023

Abstract
Transcription factor early growth response protein 2 (EGR2) prevents the development of lupus-like autoimmune disease in C57BL/6 (B6) mice by negatively regulating T cell activation, inflammatory cytokine IFNγ and IL-17 production and by suppressing humoral responses. However, increased EGR2 expression has been observed in lupus and also other autoimmune disorders, which contradicts the autoimmune suppressive role of EGR2. Here, we derived conditional EGR2−/− B6/lpr and EGR2−/− B6 mice to investigate and compare the immune regulatory role of EGR2 in autoinflammation (B6/lpr) versus normal physiological (B6) conditions. Significantly, we found that in B6/lpr mice, but not in B6 mice, EGR2 deletion dramatically suppressed serum levels of anti-dsDNA autoantibodies, total IgG, IgG1, IgG2a, and IgM. We further demonstrated that while EGR2 deletion promoted germinal center B (GCB) cell development in both B6 and B6/lpr mice, it significantly reduced the differentiation of plasma and plasmablasts cells in B6/lpr mice. EGR2 deletion promoted splenomegaly and T cell activation in both B6 and B6/lpr mice, but it differentially regulated the profiles of immune cell subpopulations in the spleens of B6 and B6/lpr mice. Especially, EGR2 deletion dramatically suppressed the development of double negative T cells in B6/lpr mice. Moreover, we found that EGR2 had an opposite role in regulating IL-17 production in in vitro activated splenocytes from B6/lpr and B6 mice, although EGR2 had a similar suppressive role for IFNγ production. Together, our data strongly suggest that the immune and autoimmune regulatory roles of EGR2 are context dependent, and should not be generalized in normal physiology and different pathological conditions.
Supported by VMCVM-VCOM Center for One Heath Research Seed Grant Program
ABCB7 is required for B cell development, proliferation, and class switch recombination
Authors: Lehrke Michael Jonathan , Shapiro Michael J , Rajcula Matthew , Theodore Keith , Lee Hyun Se Kim , Shapiro Virginia Smith 
Published: January 2023

Abstract
Iron-sulfur (Fe-S) clusters are cofactors essential for the activity of numerous enzymes including DNA polymerases, helicases, and glycosylases. They are synthesized in the mitochondria as Fe-S intermediates and are exported to the cytoplasm for maturation by the mitochondrial transporter ABCB7. Here, we demonstrate that ABCB7 is required for bone marrow B cell development, proliferation, and class switch recombination, but is dispensable for peripheral B cell homeostasis in mice. Conditional deletion of ABCB7 using Mb1-cre resulted in a severe block in bone marrow B cell development at the pro-B cell stage. The loss of ABCB7 did not alter expression of transcription factors required for B cell specification or commitment. While increased intracellular iron was observed in ABCB7-deficient pro-B cells, this did not lead to increased cellular or mitochondrial reactive oxygen species, ferroptosis, or apoptosis. Interestingly, loss of ABCB7 led to replication-induced DNA damage in pro-B cells, independent of VDJ recombination, and these cells had evidence of slowed DNA replication. Interestingly, ABCB7 appeared to be dispensable for splenic B cell homeostasis, as CD23-cre ABCB7 cKO mice had normal splenic B cell populations. However, stimulated ABCB7-deficient splenic B cells from CD23-cre ABCB7 cKO mice had a striking loss of proliferation and a defect in class switching. Thus, ABCB7 is essential for early B cell development, proliferation, and class switch recombination.
Supported by 1R21 AI157328-01 to V.S.S., T32AI007425 to M.J.L.
Regulation of metabolism by protein modifications in autoimmunity
Authors: Yang Mei-Ling , James Eddie A , Overbergh Lut , Herold Kevan C , Mamula Mark J 
Published: January 2023

Abstract
In type 1 diabetes (T1D), inflammation and oxidative stress in pancreatic islets amplifies various post-translational modifications (PTMs) of self-proteins. The loss of immune tolerance to islet PTMs triggers an autoreactive T cell response and contributes to the destruction of insulin-producing beta cells in T1D. The major function of beta cells is to secret insulin in response to glucose uptake in order to maintain glucose homeostasis. In this study, we identify autoantibodies against to beta subunit of prolyl-4-hydroxylase (P4Hb; native and carbonylated form) and glucokinase (GK; native and citrullinated form) in both human T1D and murine models. Glucokinase serves as a glucose sensor to initiate glycolysis and insulin signaling in beta cells. P4Hb is required for the accurate folding of insulin. By mass spectrometry, six carbonyl residues and eleven citrulline residues were mapped in oxidative rhP4Hb and PAD-treated rhGK, respectively. Of interest, autoreactive CD4+ T cells to citrullinated GK epitopes are present in the circulation of T1D patients. In regards to glucose metabolism, the carbonylated-P4Hb is amplified in stressed human islets coincident with decreased glucose-stimulated insulin secretion and disturb (increase) proinsulin to insulin ratios. The citrullination alters GK biologic activity (Km) and suppresses glucose-stimulated insulin secretion. Moreover, PAD2/4 inhibitors can partially restore IFNg +IL-1b suppressed glucose stimulated insulin secretion in INS-1E beta cells. Our studies implicate the crucial enzymes, glucokinase and P4Hb, as the biomarkers, providing new insights into creating autoantigens and define the impact of metabolic PTMs on the aberrant beta cell functions of T1D.
This research was supported by the Juvenile Diabetes Research Foundation (Innovative Grant to M.J.M., 2-SRA-2018-551-S-B to E.A.J.), and National Institutes of Health (DK104205-01 to K.H. and M.J.M.).
Blocking the Migration of Circulatory T cells Mitigates the Accumulation of Allergen-induced Tissue-Resident Memory T cells
Authors: Sethi Gurupreet Singh , Croft Michael 
Published: January 2023

Abstract
Targeting lymphocyte egress from lymph nodes with S1PR agonists has been approved for multiple sclerosis and colitis, but their potential in asthma is unclear. Tissue-resident memory CD4 T cells (Trm) are thought to be a major contributor to asthma relapse but the role of circulatory T cells is not fully understood. We used a murine model of house dust mite allergen-driven asthma exacerbation and transient i.v. injection of antibody and the Trm markers CD44hi CD62Llo and CD69+ to distinguish lung-localized CD4 T cells from circulatory T cells. Trm were retained in lungs after the initial allergen encounter and expanded upon repeated allergen exposures. To determine the role of circulatory T cells, mice were given FTY720, a S1PR agonist. Blocking the primary migration of circulatory T cells alleviated the formation and accumulation of lung Trm. Even so, subsequent allergen challenges still resulted in strong Trm accumulation. This was blocked if FTY720 was also given during allergen re-exposure showing that new allergen-driven circulatory T cells formed this lung Trm pool at times well after the initial sensitization. In contrast, once lung Trm cells developed at high frequency, they no longer relied on circulatory T cells with their expansion and further survival of the Trm pool being unaffected by FTY720. Overall, this suggests that targeting circulatory T cells during allergen insults might be employed to inhibit the accumulation of lung Trm in individuals with recent-onset asthma and may promote long-lasting airway tolerance. However, in individuals that have had asthma for some time and developed a stable population of lung Trm, targeting circulatory T cells may be ineffective in reducing the pathogenic T cell pool that maintains disease
Systemic bile acids potentiate airway hyperresponsiveness and modulate Th17 cell function in obesity-associated asthma
Authors: Manni Michelle L , Heinrich Victoria A , Uvalle Crystal E , Manuel Allison , Ellgass Madeline R , Mullett Steven J , Normann Marigny C , Koziel Corrine , Fajt Merritt L , Wenzel Sally E , Holguin Fernando , Freeman Bruce A , Wendell Stacy L 
Published: January 2023

Abstract
Obesity-associated asthma is phenotypically characterized by low grade inflammation and resistance to standard therapies. Like many other asthma endotypes, the molecular mechanisms contributing to obesity-associated asthma are diverse and ambiguous. A panoply of metabolites that act as signaling mediators are altered by obesity and may also promote lung dysfunction and a pro-asthma phenotype. Recent metabolomics studies indicate that bile acid profiles are altered in individuals with asthma, thus these metabolites were investigated in a murine model of obesity-associated asthma and clinically. In obese mice with allergic airway disease (AAD), the levels of β-muricholic acid (βMCA) and tauro-β-muricholic (tβMCA) were significantly increased in serum and positively correlated with impaired lung function. Two conjugated bile acids, glycocholic acid (GCA) and glycoursodeoxycholic acid (GUDCA), were elevated in the plasma of high body mass index (BMI) individuals and correlated with both BMI and airway hyperreactivity as measured by FEV1, forced expiratory volume in one second. In vitro differentiated T helper (Th) cells were treated with tβMCA and βMCA, which resulted in changes in T cell metabolism that were specific to Th17 cells. In addition, tβMCA treatment increased IL-17 production from Th17 cells upon stimulation. Finally, the anti-inflammatory and metabolic regulatory activities of nitro-oleic acid (NO2-OA) were evaluated in the murine model of obesity-associated asthma. NO2-OA reduced levels of βMCA and tβMCA, with a concomitant reduction in tissue resistance and elastance, providing a potential approach to improving the current standard of care for obese individuals with asthma.
Supported by R01HL146445 (MLM), S10OD023402 (SGW), R61HL157069 (SGW, BAF, FH), R01HL132550 (BAF)
Androgen receptor signaling decreases glutaminolysis in Th17 cells to reduce airway inflammation in asthma
Authors: Chowdhury Nowrin U , Cephus Jacqueline-Yvonne , Voss Kelsey , Gandhi Vivek D , Peebles Ray S , Rathmell Jeffrey C , Newcomb Dawn C 
Published: January 2023

Abstract
Women have higher rates of severe asthma compared to men. Severe asthma has increased Th2-mediated eosinophilic and/or Th17-mediated neutrophilic airway inflammation. We showed androgens, signaling through the androgen receptor (AR), decreased Th2- and Th17-mediated airway inflammation, and that Th17 and Th2 rely on glutaminolysis during allergic airway inflammation. Therefore, we hypothesized that AR signaling decreases glutaminolysis in Th2 and Th17 cells, resulting in decreased airway inflammation. Th2 and Th17 were differentiated in vitro from wild-type male and ArTfm male mice, with a nonfunctional AR. Mitochondrial metabolism and glycolysis were determined by measuring oxygen consumption rate (OCR), reactive oxygen species (ROS), and the extracellular acidification rate (ECAR). In Th17 cells, AR signaling decreased OCR, while increasing mitochondrial ROS, suggesting decreased glutaminolysis. Further, both 5α-DHT (0.1nM) and CB839 (a glutaminase inhibitor, 0.5μM) reduced OCR in Th17 cells from male mice. AR signaling had no effect on ECAR in Th17 cells or OCR and ECAR in Th2 cells. To induce eosinophilic and neutrophilic airway inflammation, house dust mite (HDM) was intranasally administered to Arfloxed CD4-Cre and Arfloxed male mice and markers of glycolysis and glutaminolysis were determined by flow cytometry. AR signaling decreased airway neutrophils, the number of Th17 lung cells, and GLUD1, a glutaminolysis marker, expression in T cells, but had no effect on eosinophils or Th2 cells. Combined, these data showed that AR signaling decreased glutaminolysis in Th17, but not Th2, cells. Understanding these pathways may provide new potential therapeutic targets in women with difficult-to-treat asthma.
Supported by grants from NIH (R01 HL12254, R01 HL136664, T32 GM007347)
Mouse model of late-onset neutrophilic asthma reveals an epithelium-lymphocyte-neutrophil communication circuit underlying destructive airway neutrophilia.
Authors: Shenoy Anukul T , Korkmaz Filiz , De Ana Carolina Lyon , Odom Christine , Barker Kimberly , Goltry Wesley , Ramanujan Aditya , Martin Ian , Shao Feng-Zhi , Jones Matthew , Quinton Lee , Fine Alan , Chen Felicia , Belkina Anna , Mizgerd Joseph 
Published: January 2023

Abstract
While childhood-onset asthma is extensively modeled in labs and includes TH2 cell driven-, steroid-responsive, eosinophilic etiology, little is understood about late-onset asthma which presents as severe, steroid-resistant, and destructive neutrophilic disease with poor outcomes. Lack of appropriate disease models widens this knowledge gap leading to fewer therapies and poorer quality of life for neutrophilic asthma patients. Here, we discover that while conventional models of allergic asthma (relying on naïve sensitized mice acutely challenged with aerosolized ovalbumin) induces eosinophilic asthma, transient and recurrent aeroallergenic exposure over extended durations (as would occur in humans progressing into adulthood) reprograms the lung myeloid and lymphoid landscape to instigate neutrophilic asthma. Mice with such lung history harbor diverse clusters of lung-resident CD4+ TRM cells including a novel RORγt-negative-IL17A+ TH17 subset; the latter detectable in asthmatic adult human lungs. On allergen reencounter, these RORγt-negative TH17 cells, rapidly secrete IL-17A which signals into lung epithelial and stromal cells to express CXCL5 and induce neutrophilic asthma including peribronchial neutrophilia, vascular leakage and lung damage. We find that lung epithelial antigen presentation is crucial to regulate disease severity by skewing CD4+ TRM phenotypes in asthmatic lungs. Specifically, epithelial MHC-II supports TH1 TRM cells and IFNγ secretion; the latter being a potent suppressor of IL-17A-induced CXCL5 and airway neutrophilia. Thus, using a relevant model of the disease, we identify an ‘epithelium-lymphocyte-neutrophil’ circuitry as a critical regulator of late-onset neutrophilic asthma.
Supported by NIH grants including HL147461 to F.T.K., HL142199 to K.A.B., HL136725 to M.R.J., GM120060 and HL111449 to L.J.Q., AI115053, HL135756, and HL137081 to J.P.M. and T32 HL007035 for support of trainees.