bluuebunny/crossref_metadata_2025_split huggingface dataset:
Chlamydial infection and the efficiency of MHC class I self-antigen presentation in a lymphoblastoid cell line
Authors: Simmons Ryan S , Cram Erik , Palmer Amy , Dolan Brian 
Published: January 2023

Abstract
The direct MHC class I antigen presentation pathway presents cytosolic proteins for immune surveillance. While this pathway is an attractive target for therapeutics, we must first understand the efficiency of antigen presentation. Previous studies have shown the presentation efficiency from pathogen-derived antigens ranges from 0.03–25%. The intracellular lifestyle of Chlamydia makes them an attractive model to study class I presentation. It is likely that Chlamydia have developed mechanisms to evade CD8+ T cells through manipulation of this pathway. Here, we investigate the impact of Chlamydial infection on a recombinant fusion protein expressed in a human lymphoblastoid cell line (JY). The fusion protein contains a destabilization domain, an antigenic peptide, and a reporter. Chlamydial infection led to decreased accumulation of the model protein and increased presentation of model protein-derived antigens. This enhanced self-peptide presentation was only observed when antigen presentation was restricted to the DRiP form of the protein. We also investigated the antigen presentation efficiency of different model recombinant proteins in JY cells. We calculated the antigen presentation efficiency to be 0.35%, much lower than was previously observed in murine cells with a similar protein. The skewed antigen presentation phenotype observed following Chlamydial infection was not statistically different from the efficiency observed in the absence of infection. These data suggest that Chlamydia have evolved a mechanism to skew the host antigen presentation machinery toward presentation of DRiPs, and that the efficiency of direct class I presentation may be mechanistically unique among common immune signaling pathways.
Fetal and adult progenitors give rise to unique populations of CD8+ T cells
Authors: Wang Jocelyn , Wissink Erin , Smith Norah L. , Grimson Andrew , Rudd Brian D 
Published: January 2023

Abstract
Neonates often generate incomplete immunity against intracellular pathogens. As CD8+ T cells are essential in clearing intracellular infections, it is crucial to understand how neonatal CD8+ T cells respond to infection. We showed that neonatal CD8+ T cells fail to form memory. However, the underlying basis for this is unclear. Here, we investigated whether neonatal CD8+ T cells fail to form memory cells because (i) they have undergone more extensive homeostatic proliferation (HP) prior to infection (proliferation model) or (ii) they are created from a distinct hematopoietic stem cell (HSC) population (origin model). We first compared the behavior and gene expression profiles of different aged CD8+ T cells that had undergone similar amounts of HP. Interestingly, neonatal CD8+ T cells still possessed unique gene expression profiles and failed to form memory post-infection. Hence, the proliferation model cannot fully explain the differences. We tested the origin model by comparing neonatal and adult CD8+ T cells at the same stage of thymic development. Again, we observed distinct gene expression profiles, indicating that CD8+ T cells are created differently in neonates. To examine whether different HSCs underlie these differences, we adoptively transferred fetal and adult progenitors into adult thymii and found that fetal progenitor derived CD8+ T cells exhibited a memory phenotype and selectively formed short-lived effectors after infection. The adult progenitor derived cells exhibited a more naïve phenotype and preferentially formed memory precursors after infection. Collectively, our data extends the layered immune hypothesis to CD8+ T cells and suggests that neonatal and adult CD8+ T cells are derived from different HSCs.
Activation of Complement Factor B Contributes to Murine and Human Myocardial Ischemia/Reperfusion Injury
Authors: Zhang Ming , Haddadin Ala , Hou Yunfang , Wong Karen , Liu Junying , Chun Nicholas , Rushbrook Julie , Hines Roberta , Nuno Beatriz Nistal , Pekna Marcela , Patel Foramben , Shevde Ketan , Heeger Peter S 
Published: January 2023

Abstract
The pathophysiology of myocardial injury resulting from cardiac ischemia and reperfusion (I/R) is incompletely understood. Experimental evidence from murine models indicates that innate immune mechanisms including complement activation via the classical and lectin pathways are crucial. Whether factor B (fB), a component of the alternative complement pathway required for amplification of complement cascade activation, participates in the pathophysiology of myocardial I/R injury has not been addressed. We induced regional myocardial I/R injury by transient coronary ligation in WT mice, a manipulation that resulted in marked myocardial necrosis associated with upregulated myocardial expression of fB gene, activation of fB protein, and myocardial deposition of C3 activation products. In contrast, in fB−/− mice, the same procedure resulted in significantly reduced myocardial necrosis and diminished deposition of C3 activation products in the myocardial tissue. To extend the analysis to humans we measured levels of activated fB (Bb) in intracoronary blood samples obtained during cardio-pulmonary bypass surgery before and after aortic cross clamping (AXCL), during which global heart ischemia was induced. Intracoronary Bb increased immediately after AXCL, the levels were directly related to the length of the AXCL and correlated with peripheral blood levels of cardiac troponin I, an established biomarker of myocardial necrosis. Taken together, our results support the conclusion that fB is a crucial pathophysiological amplifier of I/R-induced, complement-dependent myocardial necrosis and identify fB as a potential therapeutic target for prevention of human myocardial I/R injury.
Bisphenol A (BPA) and Bisphenol S (BPS) increase Coxsackievirus B3 myocarditis in female and male BALB/c mice by activating mast cells, increasing immune cell infiltrate and activating the inflammasome
Authors: Bruno Katelyn A , Yang Alex , Mathews Jessica , Greyner Henry , Molina Frank , Bucek Adriana , Fairweather DeLisa 
Published: January 2023

Abstract
Myocarditis is an inflammatory heart disease that is the leading cause of heart failure in young adults. Sex hormones play a vital role in development of myocarditis with testosterone driving disease in males. Whereas, estrogen, via Estrogen Receptor α (ERα) mediates cardioprotection in females. Since myocarditis is influenced by sex hormones, it is highly probable that endocrine disruptors (EDs); which interfere with natural hormones, will play a part in the progression of the disease. The human population is exposed to Bisphenol A (BPA), a known ED that binds the ER, from plastics, such as water bottles and plastic food containers. BPA could increase myocarditis through deleterious actions of the ERβ rather than beneficial effects via ERα. To our knowledge no one has examined the role of EDs like BPA on myocarditis. We found that clinically relevant doses (25 μg/L and 250 μg/L) of BPA increased acute myocarditis compared to control water in females. In females we found BPA significantly decreased ERα, while ERβ was significantly increased. We found that mast cells (cKit) are largely responsible for the increase in inflammation along with CD4 Thelper cells, IL-1β, IFN-γ, TLR4, Caspase-1, Mmp9, and ST2. In male mice, we found that at the high dose of BPA increased myocarditis and increased all immune cell markers and the inflammasome. We also investigated the compound Bisphenol S (BPS) which has replaced BPA in a number of products and found that BPS also increases myocarditis. Interestingly this effect was only seen in Balb/c mice and not BL/6 suggesting that race could be a factor in evaluating ED role in disease. We have found that ED exposure is having a significant effect on myocarditis and could potentially influence a number of human diseases.
Human Gingiva-Derived Mesenchymal Stromal Cells Inhibit Graft-versus-Host Disease through CD39 and IDO
Authors: Wang Julie , Chen Maogen , Chen Weiqian , Olsen Nancy J , Zheng Song Guo 
Published: January 2023

Abstract
Mesenchymal stem cells (MSCs) have the capacity to maintain immune homeostasis and prevent autoimmunity. However, it is unclear whether human-derived gingival mesenchymal stem cells (GMSCs) can suppress human T cell-mediated diseases. GMSCs were isolated from human gingival tissues. GMSCs were cultured with allogeneic T cells which labeled with CFSE, and cell proliferation was evaluated by CFSE dilution in FACS. In other experiments, human PBMCs were stimulated with LPS with a ratio of PBMCs to GMSCs at 1:5. After 3 days, intracellular cytokine including IL-4, IL-17, and IFN-γ in CD4+ cells were determined by FACS. Mouse xeno-GVHD Model was induced in NOD/SCID mice, GMSCs or human fibroblasts (negative control) or human bone marrow mesenchymal stem cells (positive control) were intravenously into mice. Weight loss and symptoms of GVHD were assessed. We observed that GMSCs potently suppress the proliferation of T cells and differentiation of PBMC in vitro, and that co-transfer of GMSC but not fibroblast and human PBMC significantly prolonged xeno-GVHD mouse survival. We also demonstrated that GMSC is even better than BMSC on treating xeno-GVHD. We further revealed that GMSCs inhibit human PBMCs-initiated xenogenic responses via CD39 and IDO signals. GMSCs can suppress human immune responses and immune system-mediated diseases, offering a potential clinical option to be used for modulating GVHD and other autoimmune diseases.
Long-range transcriptional effects and specific epigenetic marks in regulation of transcription from Lck proximal and distal promoters
Authors: Chiang Jeffrey , Hodes Richard J 
Published: January 2023

Abstract
Lck is a critical molecule for T cell development and activation. The T cell-specific expression of Lck is controlled by two distinct promoters separated by 15kb. The proximal promoter contributes the majority of Lck transcripts in immature thymic T cells, while the distal promoter expresses the majority of Lck transcripts in mature T cells. To study the regulation of these two promoters, promoter-mutated mouse models were generated by CRISPR technology, resulting in multiple mouse lines with distinct promoter deletions. The activity of the proximal promoter was reduced by 95% in the DP thymocytes of PROX[mut] mice with ~100bp deletion in the proximal promoter. Expression of distal-promoter-driven Lck mRNA was completely abrogated in immature and mature T cells in Lck distal promoter DIST[mut] mice with partial deletion of the distal promoter and exon 1. Distal-promoter-driven Lck mRNAs were not altered in PROX[mut] mice. However, proximal-promoter-driven Lck mRNAs were dramatically increased in the mature T cells of DIST[mut] mouse, suggesting that there is a long-range transcriptional interaction between the two promoters. To further understand the epigenetic influences in Lck gene expression, we analyzed histone modifications in the regions of Lck promoters. Our preliminary data showed the distal promoter was highly H3K9 acetylated in peripheral T cells but not immature T cells, and that this acetylation was decreased in DIST[mut] mice. Therefore, distal promoter H3K9 acetylation was correlated with promoter activity and may be involved in the developmental stage specificity of Lck promoters. The findings of this study on Lck promoters may provide important information on gene expression and its tissue-specificity.
The histone demethylase LSD1 inhibits PD-1 expression in acute viral infections
Authors: Bally Alexander , Austin James W , Lu Peiyuan , Boss Jeremy 
Published: January 2023

Abstract
During immune responses against chronic viral infection or cancer, expression of the immune-inhibitory receptor Programmed cell death-1 (PD-1) on T cells results in cellular exhaustion, characterized by poor cellular immune functions ultimately leading to a failure to respond appropriately to antigen. Intriguingly, exhausted PD-1hi cells from a chronic infection remain exhausted even after removal from chronic antigen exposure, indicating an active epigenetic mechanism is employed to inhibit PD-1 expression. This study elucidates the role of the histone H3K4me1/me2 demethylase LSD1 in mediating epigenetic changes at the PD-1 locus which lead to gene silencing. Blimp-1, a known inhibitor of PD-1 that associates with epigenetic modifiers, was bound to the locus in CD8 T cells during both acute and chronic modes of infection. However, LSD1 was only recruited during acute infection concurrent with PD-1 silencing. Accordingly, the active histone modifications H3K4me1 and me2, which are removed by LSD1, were absent after acute but not chronic infection. PD-1 expression on T cells was enhanced and prolonged during acute infections in an LSD1 conditional knockout mouse. Expansion of these studies to an in vivo melanoma model also showed that loss of LSD1 resulted in higher expression of PD-1 on tumor-infiltrating lymphocytes, and a corresponding failure to clear tumor cells. Together these data highlight a distinct role for LSD1 as a defining factor mediating the silencing of PD-1 expression following acute immune activation. This study elucidates a key epigenetic mechanism governing the switch in cell fate between acute effector or exhausted T cell, and highlights the overall role that epigenetics play in modulating immune responses.
Zbtb-1 controls NKp46+RORgammat+ innate lymphoid cell (ILC3) development.
Authors: Lu Ying , Zhang Xianyu , Bouladoux Nicolas , Belkaid Yasmine , kovalovsky Damian 
Published: January 2023

Abstract
Innate lymphoid cells (ILCs) play a central role in conferring protective immunity at the mucosal frontier. We identified a new function of the transcription factor Zbtb1 for the development of RORgammat+ ILCs (ILC3s). Zbtb1-deficient mice lacked NKp46+ ILC3 cells in the lamina propria of the small intestine and colon, which was consequence of impaired development of its RORgammat+ CCR6−NKp46− progenitors. This requirement of Zbtb1 was cell intrinsic as it was observed in in vitro developmental co-cultures with OP9-DL1 stroma and in vivo in bone marrow chimeras. The ILC3 developmental defect correlated with inefficient upregulation of T-bet expression and, as consequence, ILC3 cells from Zbtb1-deficient mice failed to acquire IFN-γ and repress IL-22 production upon development into NKp46+ cells. In correlation with a lack of NKp46+ILC3 cells, Zbtb1-deficient mice presented increased susceptibility to C.Rodentium infections. Altogether, these results establish that Zbtb1 is essential for the development of NKp46+ ILC3 cells.
Role of CCR10 and CCL27 in skin resident T cell development and homeostasis
Authors: Davila Micha L , Fu Yaoyao , Yang Jie , Xiong Na 
Published: January 2023

Abstract
The skin hosts numerous immune cell subsets which generate synergistic responses to a variety of stimuli including foreign antigens, pathogens and commensal bacteria. Each stimulus is unique and calls for a specific and balanced response; any disruption of this homeostasis can lead to complications such as inflammatory diseases. T cells in the skin are a key player in the response to infection, maintenance of commensal bacterial, and tissue homeostasis. Thus, elucidating the mechanisms regulating T cell migration, establishment, and maintenance within the skin is a high priority. CCR10, a receptor expressed on the majority of skin resident T cells, has a complex role in the development of skin-resident T cells through interaction with its skin-specific receptor CCL27. Preliminary data from our analysis of T-cell specific phenotypes in CCL27a knockout mice demonstrates a preferential reduction of Treg cells in the skin, highlighting the importance of CCL27a in the establishment of skin resident Treg cells under homeostatic conditions. Furthermore, we found CCR10+ resident CD8+ T cells contribute to the homeostatic maintenance of Treg and CD4+ effector T cells in the skin. Defective establishment of CCR10-knockout CD8+ T cells in the skin was shown to correlate with a reduction of skin-resident Treg cells. Skin-resident CD8+ T cells express high amounts of B7.2, a ligand for CTLA-4 which is highly expressed on Treg cells in the skin. In vitro co-culture of purified skin CD8+ and Treg cells suggests B7-2/receptor interaction is important for CD8+ cell-mediated survival of Treg cells. These findings will greatly aid in further understanding the development and homeostasis of skin resident T cells.
IL-33 mediated expansion of host ST2+ Treg prior to allogeneic hematopoietic cell transplantation decreases macrophage and effector T cell activation reducing acute GVHD
Authors: Reichenbach Dawn K , Matta Benjamin M , Zhang Xiaoli , Koehn Brent , Mathews Lisa , Smith Michelle J , Feser Colby J , Zeiser Robert , Turnquist Heth Roderick , Blazar Bruce R 
Published: January 2023

Abstract
Graft-versus-host disease (GVHD) is the leading complication and cause of mortality after allogeneic hematopoietic cell transplantation (allo-HCT). Recently, we reported that IL-33 released from tissue damaged during allo-HCT conditioning mediates pro-inflammatory responses by Teffector cells resulting in greater acute GVHD lethality and clinical symptoms in mice. However, IL-33 is a pleiotropic cytokine that mediates both pro-inflammatory and anti-inflammatory responses. We hypothesized that the beneficial effects mediated by IL-33 could be harnessed if IL-33 was present prior to inflammatory mediators released during conditioning. Here, we demonstrate that exogenous IL-33 given peri allo-HCT (days −10 to 4) to recipients of MHC-disparate allo-HCT asserts its immunoregulatory properties reduced GVHD lethality and clinical symptoms compared to non-treated controls. IL-33 treatment peri allo-HCT resulted in the expansion of recipient Treg and suppressive myeloid cells that persisted post irradiation. Host Treg depletion in C57Bl/6 FoxP3-DTR mice by diphtheria toxin given concurrently with peri allo-HCT IL-33 treatment accelerated GVHD symptoms and lethality compared to peri allo-HCT IL-33 treatment alone, demonstrating that host Treg were necessary for GVHD protection. Transfer of Treg deficient in ST2, the IL-33 receptor, afforded less GVHD protection than wild-type Treg. ST2+ Treg controlled macrophage activation and prevented accumulation of Teffector cells in GVHD target tissue. Thus, we demonstrate that peri allo-HCT IL-33 expanded and activated host Treg have potential as a therapeutic modality to prevent and treat GVHD.
Serine protease inhibitor 6 protects allogeneic T cells from granzyme B-mediated mitochondrial damage without impacting graft-versus-tumor effect.
Authors: Du Wei , Kumar Sandeep , O’Neill Rachel , Chen Chuan , Mei Lin , McCarthy Philip , Cao Xuefang 
Published: January 2023

Abstract
Allogeneic hematopoietic cell transplantation(allo-HCT) is a potentially curative therapy for hematologic malignancies. Donor T cells are able to eliminate residual tumor cells in the host after allo-HCT, producing the beneficial graft-versus-tumor (GVT) effect, but can also causegraft-versus-host disease (GVHD) when attacking host normal tissues. We previously reported that granzyme B (GzmB) is involved in activation induced celldeath (AICD) of donor T cells and exerts differential impacts on GVHD and GVT effect. Serine protease inhibitor 6 (Spi6) is the sole endogenous inhibitor of GzmB that can protect immune and tissue cells against GzmB-mediated damage. Now this study is aimed to delineate the mechanism by which the GzmB-Spi6 axis regulates allogeneic T cell response. We have found that Spi6 is concentrated in mitochondria during allogeneic T cell activation, while Spi6−/− T cells exhibit abnormal mitochondrial membrane potential, mass, reactive oxygen species (ROS) production and increased GzmB-dependent AICD. Compared with WT T cells, Spi6−/− T cells exhibit decreased expansion in the host and cause significantly reduced GVHD. Notably, however, Spi6−/− T cells demonstrate the same level of GVT activity as WT T cells. These results suggest that Spi6 protects allo-reactive pathogenic T cells from GzmB-mediated mitochondrial damage but is dispensable for tumor-reactive T cells mediating GVT effect, probably due to its differential expression in these T cells. In sum, our data demonstrate that Spi6 playsa novel and critical role in maintaining T metabolism during allogeneic response, and suggest that disabling Spi6 in donor T cells may represent a novel strategy that can alleviate GVHD without sacrificing GVT effect.
Tumor-associated CAIC5 suppresses NKT cell proliferation and cytokine production
Authors: Choi Inhak , Lee Eungchang , Jung Keunok , Kim Heejung 
Published: January 2023

Abstract
In the previous study, we identified cancer-associated immune checkpoint 5 (CAIC5) as a new co-inhibitory molecule belonging to B7-related family. Typically, CAIC5 is expressed in tissue macrophages including Kupffer cells and peritoneal macrophages. We also found out human CAIC5 fusion protein greatly suppressed the proliferation and cytokine production in T cells and NKT cells in a respective stimulation assay. Since CAIC5 expression was identified in tumor microenvironment, we examined the impact of tumor cell-associated CAIC5 on NKT cell function. CAIC5-expressing cancer cells that are pulsed with alpha-galactosylceramide (a-Gal) greatly suppressed NKT cell IFN-g production and proliferation. CAIC5 KO mice that were systemically injected with a-Gal enhanced IFN-g production in NKT cells. Furthermore, WT mice that were injected with CAIC5-expressing tumor cells showed a poor survival compared to those with mock-expressing cells. We also found out human NKT cells were similarly suppressed in IFN-g production in the coculture with CAIC5-expressing cancer cell line. Therefore, tumor CAIC5 can be an important part of mechanisms for cancer immune escape.
In vitro and in vivo characterization of small molecule inhibitors of the anti-inflammatory TAM receptor MerTK
Authors: Owyang Alexander , Holland Sacha , Yi Sothy , Young Chi , Braselmann Sylvia , Frances Roy , Bagos Art , Tai Ernie , Siu Stacey , Park Gary , Lau David , Duan Matt , Yu Jiaxin , Ding Pingyu , Kolluri Rao , Bhamidipati Somasekhar , Darwish Ihab , Singh Raj , Payan Donald G , Masuda Esteban S 
Published: January 2023

Abstract
MerTK, a TAM (Tyro3, Axl, MerTK) family RTK, is expressed on phagocytic cells. Its normal function is to dampen innate immune responses to self-antigens. MerTK is an indirect phosphatidylserine (PtdSer) receptor: PtdSer-binding TAM ligands (Gas6 or Protein S) bridge interactions between MerTK and PtdSer externalized on apoptotic cells (ACs), resulting in AC internalization (efferocytosis). Ensuing MerTK signaling leads to anti-inflammatory M2 macrophage polarization, suppression of pro-inflammatory cytokine production, and a tolerogenic outcome.
Tumors are rich in ACs and TAM ligands. Syngeneic tumors implanted in MerTK −/− mice exhibit impaired growth and metastasis compared with those implanted in WT mice. Moreover, MerTK aberrantly expressed on hematological and epithelial malignancies promotes survival and chemoresistance. Thus, pharmacological inhibition of MerTK may have clinical benefit by increasing availability of dead tumor cell antigens, blocking tumor-induced immunosuppression, or blocking tumor cell survival.
Here we describe novel and potent MerTK-selective and Mer-Axl small molecule inhibitors that block both MerTK in vitro kinase activity and MerTK autophosphorylation and downstream signaling in cells. Moreover, compounds were able to inhibit phagocytosis of ACs by MerTK-expressing human primary macrophages, and they block activation of MerTK in vivo. The MerTK inhibitors were not overtly cytotoxic or antiproliferative, and did not block the activity of TLR or T cell immune effector pathways. Limited off-target activity was observed in an in vitro kinase panel. Activity of these novel MerTK inhibitors in tumor models is currently under investigation.