bluuebunny/crossref_metadata_2025_split huggingface dataset:
Complement initiation and regulation differ by sex in intestinal ischemia reperfusion injury
Authors: Rowe Jennifer M , Wu Miaomiao , Fleming Sherry D 
Published: January 2023

Abstract
Males and females frequently sustain distinct symptoms during ischemic events and subsequent inflammatory events. The inflammatory events include significant complement activation, neutrophil infiltration and significant cytokine secretions. The past literature suggests that complement activation may include a sex-linked protein. Therefore, we hypothesized that complement activation may vary by sex during intestinal ischemia/reperfusion (IR) injury. We subjected male and female mice to 30 min intestinal ischemia followed by 15, 30, 60 or 120 min reperfusion. Additional mice of each sex was subjected to sham surgery. Intestinal sections were stained and complement initiation pathways and time points of deposition determined. Complement regulatory molecules were also examined. Initial results suggest that males expressed more C1q compared to females, while females expressed more MBL than males. In addition, complement regulators varied by sex. Our data demonstrate that complement initiation and regulation differ between sexes during intestinal IR. These response differences in intestinal IR provide insight into the sexual dimorphism of ischemic intestine diseases and may aid in the development of sex-specific therapies that reduce intestinal injury.
Regulation of STING Trafficking and Interferon Response
Authors: Tu Xintao , Chu Ting-ting , Yan Nan 
Published: January 2023

Abstract
STING is an endoplasmic reticulum (ER)-associated transmembrane protein that is essential for the host innate immune response to pathogens. STING is activated by the second messenger cyclic dinucleotides which is produced from the invading pathogen or by the host DNA sensor cGAS. Activation of STING triggers its trafficking from the ER, through ERGIC/Golgi, to vesicles, during which time STING activates and quickly terminates downstream interferon signaling. Despite the importance of STING signaling in infection, autoimmune disease and cancer immunotherapy, the dynamics of STING trafficking and kinetics of signaling are poorly understood. Here, we performed a time-resolved proteomic screen to capture protein interaction networks of STING during its trafficking process. We also established a synchronized live-cell microscopy technique that allows us to define changes in protein trafficking kinetics. We have identified several co-factor candidates that affect various steps of the STING trafficking and signaling. Collectively, our findings revealed the previously unanticipated the regulation of STING trafficking as well as its downstream signaling by the host factors in the secretory pathway.
Cirsium japonicum var. ussuriense extract and cirsimaritin prevents the expressions of IL-17 in high-fat diet induced non-alcoholic steatohepatitis
Authors: Jang Seon Il , Choi Jiwon , Cho Byoung Ok , Kang Hyun Ju , Che Denis Nchang , Shin Jae Young 
Published: January 2023

Abstract
Nonalcoholic fatty liver disease (NAFLD) corresponds to hepatic manifestations of inflammation and accumulations of fatty acids in the liver. Recently, IL-17 signaling pathways have been shown to contribute to the pathogenesis of NAFLD. Cirsium japonicum var. ussuriense is often used in treatment of human diseases such as hemorrhage, blood congestion and inflammation. Despite the known biological activities of C. japonicum var. ussuriense, its effect on NAFLD is still unknown. Here, we investigated the effects of C. japonicum var. ussuriense extract (CJE) and cirsimaritin, its main constituents, on high-fat diet (HFD) or oleic acid (OA)-induced IL-17 expressions associated with steatohepatitis. We found that the levels of IL-17 was reduced in OA-treated HepG2 cells and in mice fed with HFD and administered with CJE and cirsimaritin at the mRNA, protein, and serum expression levels. Further investigation showed that CJE and cirsimaritin suppressed MAPK and NF-κB, the key signaling pathway responsible for IL-17 expression in HFD-fed mice and OA-treated hepatocytes, thus suggesting that the action of CJE and cirsimaritin on signaling molecules might have been responsible for the suppression of IL-17. Here, we also demonstrated that administration of CJE and cirsimaritin reduced triglyceride, aspartate aminotransferase, alanine aminotransferase, and malondialdehyde levels in OA-treated HepG2 cells; and protected mice against HFD-induced triglyceride, aspartate aminotransferase, alanine aminotransferase, and malondialdehyde levels. The results collectively demonstrate that CJE and cirsimaritin may protect against IL-17 exacerbated HFD-induced steatohepatitis.
Polyubiquitin-dependent recruitment of NEMO/IKKγ into T cell receptor signaling microclusters is controlled by IKKβ kinase activity
Authors: Koylass Nicholas Robert , DeRiso Elizabeth , Szymczak-Workman Andrea L , Montecalvo Angela , Murphy Joanne M. , Seminario Maria-Cristina , Bunnell Stephen C , Kane Lawrence P 
Published: January 2023

Abstract
The IkB kinase (IKK) complex coordinates inflammatory responses by activating canonical NFkB downstream of immune receptors. This complex consists of the kinases IKKa/β and the dimeric adaptor subunit NEMO (NFkB essential modulator protein). NEMO mutations cause immunodeficiencies and impair antigen receptor function. Canonical NFkB activation by immunoreceptors, such as the T cell receptor (TCR), requires the assembly of the Carma1/Bcl10/Malt1 (CBM) signalosome. While, functional studies and in vitro interactions, place the IKK complex downstream of the CBM signalosome, the spatial relationship between these complexes has never been observed in intact immune cells.
We observed that NEMO is recruited into TCR microclusters and membrane compartments within ~70 seconds of TCR engagement. Point mutations impacting the K63-linked and linear polyubiquitin ubiquitin-binding domains of NEMO selectively impair NEMO recruitment into TCR microclusters. We verified the involvement of these polyubiquitin chains by showing that inhibitors of either the K63-specific Uev1A/Ubc13 ubiquitin E2 ligase or the linear ubiquitin activating complex (LUBAC) prevent NEMO from entering TCR microclusters. To examine whether the entire IKK complex is recruited to the TCR, we co-expressed IKKb chimeras with NEMO. We observed that wild-type (WT), but not kinase-dead, IKKb caused NEMO microclusters to disappear. Similarly, the treatment of cells expressing WT IKKb with inhibitors of IKKβ or its upstream activator, TAK1, restored the recruitment of IKKβ and NEMO into microclusters.
These results suggest that the IKK complex is recruited to the TCR via linear- and K63-linked polyubiquitin chains and then dissociates from the TCR via IKKβ activity.
Diapedesis and LFA-1 mediate tissue immune cell effector activity via intrinsic complement C3 licensing
Authors: Kemper Claudia , Kolev Martin , West Erin E , Kunz Natalia , Rahman Jubayer , Chauss Daniel , Moutsopoulos Niki , Holland Steven M , Kaplan Mariana J , Wang Luopin , Kazemian Majid , Afzali Behdad 
Published: January 2023

Abstract
Intracellularly generated and autocrine-functioning complement component C3 is a critical integral part of normal human CD4+ Th1 and cytotoxic CD8+ T cells responses. Increased or decreased intracellular C3 result in autoimmunity and infections, respectively. The mechanisms regulating intracellular C3 expression are, however, undefined. By comparing transcriptomes from blood and tissue, we identified the complement system, including C3, as one of the most significantly enriched biological pathways in tissue-occupying cells of human macrophages, CD4+ and CD8+ T cells. By leveraging a novel C3 reporter mouse, we confirmed that C3 gene transcription is a feature of immune cells in tissues, is induced during trans-endothelial diapedesis, and is dependent on the integrin intercellular adhesion molecule (ICAM)-1 liganding lymphocyte function-associated antigen (LFA)-1. Consequently, monocytes and T cells from patients with leukocyte adhesion deficiency (LAD)-1 had reduced C3 and diminished effector activities, which could be rescued proportionally by normalization of intracellular C3. In synovia of patients with rheumatoid arthritis (RA), C3 transcript expression by CD4+ T cells was linearly associated with disease severity and acted as a biomarker distinguishing inflamed versus uninflamed RA. Our study defines the integrin network as a novel and key controller of intracellular complement, demonstrates that perturbations in the LFA-1–C3 axis contribute to primary human immunodeficiency and identifies T cell C3 production as a biomarker of the severity of autoimmunity.
Dynamic Adoption of Anergy by Antigen-Exhausted CD4+ T Cells
Authors: Obst Reinhard , Trefzer Anne , Kadam Pallavi , Wang Shu-Hung , Pennavaria Stefanie , Lober Benedikt , Kranich Jan , Brocker Thomas , Irmler Martin , Beckers Johannes , Straub Tobias 
Published: January 2023

Abstract
Exhausted immune responses to chronic diseases represent a major challenge to global health. We studied CD4+ T cells in a mouse model where presentation of their antigen can be regulated. When the cells are driven through the effector phase, but are then exposed to different levels of persistent antigen, they lose their Th1 functions, upregulate exhaustion and anergy markers, modulate their MAP kinase, mTORC1 and Ca2+/calcineurin signaling pathways with dose and time, lose their capacity to transmit help to B cells and undergo, at the highest dose, apoptosis. Transcriptomic analyses show the dynamic adjustment of gene expression and the accumulation of TCR signals over a period of weeks. The cells also adapt to antigen removal and recover their functionality while losing exhaustion and anergy markers. Our data suggest an adjustable response of CD4+ T cells to different levels of persisting antigen and contribute to a better understanding of chronic disease.
Genome-wide CRISPR screens revealed a reciprocal role of SWI/SNF complexes in controlling regulatory T cell function
Authors: Loo Chin San , Zheng Ye 
Published: January 2023

Abstract
Regulatory T cells (Tregs) are a specialized immune population that act to suppress overactive inflammatory response and maintain immune homeostasis. There is of great interest in harnessing Treg for controlling autoimmune disease or boosting anti-tumor immunity. Since the transcription factor, Forkhead box P3 (Foxp3), is known to control Treg development and function, understanding the regulation of Foxp3 could potentially lead to the development of therapeutics for treating autoimmune diseases and cancer. Here we performed a genome-wide CRISPR/Cas9 knockout screen to identify the regulators of Foxp3 in mouse primary Tregs. The results showed that Foxp3 regulators are highly enriched in genes encoding chromatin regulators, such as SAGA and SWI/SNF complexes. Among the SWI/SNF complexes, the GBAF complex promoted Foxp3 expression, whereas the PBAF complex repressed its expression. Functional genomic studies revealed that both GBAF and PBAF co-localized with Foxp3 in genome-wide binding sites. Targeting of GBAF reduced Foxp3 binding and altered expression a subset of Foxp3 target genes, indicating that GBAF actively participates in the Foxp3-dependent transcriptional program. Importantly, Treg suppressor function can be manipulated by targeting GBAF or PBAF, demonstrating in in vitro suppression assay, as well as mouse in autoimmune diseases and tumor model. Collectively, we provide an unbiased analysis of genes and networks regulating Foxp3, and reveal SWI/SNF complexes, GBAF and PBAF, as novel targets that could be exploited to manipulate Treg function for therapeutics of autoimmune diseases and cancer.
Regulation of the JAK2/STAT3 Signaling Pathway by the Lupus Susceptibility Gene Pbx1
Authors: Roach Tracoyia A , Choi Seung-Chul , Abboud Georges , Cornaby Caleb , Morel Laurence 
Published: January 2023

Abstract
Systemic Lupus Erythematosus (SLE) is an autoimmune disease in which poorly characterized genetic factors lead to the production of autoreactive or inflammatory T cells. Pre-B cell leukemia homeobox 1 (Pbx1) is a transcription factor whose dominant negative splice isoform (Pbx1-D) is overexpressed in CD4 T cells of lupus patients and lupus-prone mice as compared to the normal isoform (Pbx1-B). Pbx1-D overexpression impairs Treg cell development and function while favoring the production of follicular helper T cells. Based on previous studies showing that Pbx1 promotes cell proliferation via JAK2/STAT3 signaling pathway in a renal cell carcinoma, we hypothesized that Pbx1-D decreases T cell proliferation and viability by attenuating the JAK2/STAT3 signaling pathway. Pbx1-B or Pbx1-D expression plasmids increased pSTAT3 protein levels but there was no difference between the two isoforms in 293T cells. U3A STAT3 reporter cells transfected with Pbx1-B plasmid have greater luciferase expression, and hence pSTAT3 transcriptional activity in comparison to cells transfected with Pbx1-D or control plasmids. We also observed that Pbx1-B increases the expression of Jak2 and Stat3 message as compared to Pbx1-D. These results suggest a mechanism by which Pbx1 contributes to impaired T cells in lupus pathogenesis is via the JAK2/STAT3 pathway. Current studies are conducted to dissect the mechanism by which Pbx1 regulates this pathway in primary T cells.
Supported by a grant from the NIH (RO1AI04505021) to LM
Elucidating roles of the Rag1 N-terminus and RAG DSBs in shaping the cellular response to TCRa recombination
Authors: Miot Charline , Arya Rahul , Burn Thomas , Behrens Edward M. , Bassing Craig 
Published: January 2023

Abstract
The RAG1/RAG2 (RAG) endonuclease generates lymphocyte antigen receptor gene diversity via V(D)J recombination. The large numbers of V, D, and J segments and inherent imprecision in repair of RAG DNA double strand breaks (DSBs) together establish a vast diversity of antigen receptor specificities, including self-reactive receptors. Mechanisms have evolved to negatively select self-reactive cells and inhibit autoimmunity. In humans, deletion of the RAG1 N-terminus causes Omenn Syndrome, a fatal immunodeficiency with ab T cell-based autoimmunity. We discovered impaired negative selection in a spontaneous homozygous Rag1 mutant mouse with loss of the Rag1 N-terminus. This Rag1 region, which is not required for V(D)J recombination, has intrinsic ubiquitin ligase activity and interacts with another ubiquitin ligase and a kinase. We hypothesize the RAG1 N-terminus signals from RAG DSBs induced during TCRa recombination to shape the thymocyte proteome and enhance negative selection. To test our hypothesis, we have made mice whose thymocytes lack RAG DSBs or harbor RAG DSBs induced by wild-type Rag1 or mutant Rag1 lacking the N-terminus or intrinsic ubiquitin ligase activity. Our preliminary data suggest that RAG DSBs and distinct RAG1 N-terminus activities up-regulate expression of Zap70, an intracellular protein that transmits TCR signals, and CD80, a transmembrane protein that co-stimulates T cells engaging antigen. These data are consistent with a model wherein the RAG1 N-terminus facilitates negative selection through stimulating TCR signaling in thymocytes that bind self-antigens presented by thymocytes, dendritic cells, or thymic epithelial cells.
CD49a mediates cutaneous resident memory CD8+ T cell persistence and response
Authors: Bromley Shannon K , Akbaba Hasan , Mani Vinidhra , Mora-Buch Rut , Chasse Alexandra Y , Luster Andrew D 
Published: January 2023

Abstract
Resident memory CD8+ T cells (TRM) persist at sites of previous infection where they provide rapid local protection against pathogen challenge. CD8+ TRM expressing the a1 chain (CD49a) of integrin VLA-1 have been identified within sites of resolved skin infection as well as in vitiligo lesions. This study examines the signals that regulate CD8+ T cell CD49a expression and its requirement for cutaneous TRM formation and response. We demonstrate that CD49a was expressed early following T cell activation in vivo, and that TGF-b as well as IL-12 induced CD49a expression by CD8+ T cells in vitro. Despite this rapid expression, CD49a was not required for the generation of a primary CD8+ T cell response to cutaneous herpes simplex virus (HSV) infection. Rather, CD49a mediated epidermal CD8+ TRM interaction with the extracellular matrix, supported CD8+ TRM persistence within the skin, and increased the frequency of CD8+ TRM that secrete IFN-g following local antigen challenge. Thus, our results suggest CD49a promotes optimal cutaneous CD8+ TRM-mediated immunity.
Naïve T cells surpass pre-existing memory to dominate post-vaccine responses in humans
Authors: Su Laura F. , Pan Yi-Kan , Aiamkitsumrit Benjamas , Wang Yifeng , Marc Adam , Lavery criswell , Rappazzo Garrett C. , Hensley Scott , Birnbaum Michael 
Published: January 2023

Abstract

Background
There is a critical unmet need for vaccines against emerging diseases and common infections, such as HIV, malaria, and tuberculosis. Defining the mechanisms by which memory T cell responses are generated in humans is essential for developing efficacious vaccines. We have previously described that human adults possess pre-existing memory phenotype CD4+ T cells specific for viral antigens to which they have never been expose. The goal of our study is to test how memory precursors respond to antigen challenge and to identify other key aspects of the human precursor repertoire that are required for a robust vaccine response.

Methods
We are using yellow fever virus (YFV) vaccination as a model to examine the link between precursor T cell composition and cellular response to cognate antigen stimulation. We screened study participants for HLA allele of interest and the absence of prior exposure to YFV by serology. We then use peptide-MHC tetramers to identify YFV-specific T cells before vaccination and at multiple time points after YFV vaccination.

Results
Direct ex vivo analyses of YFV-specific CD4+ T cells in the blood revealed three key observations. First, precursor T cells vary in size, but a larger precursor frequency does not predict better post-vaccination response. Second, naïve precursors outcompete memory precursors to generate a larger effector population. Third, the magnitude of effector cell frequency predicts clonotypic selection into the stable memory pool.

Conclusions
Durable memory response to primary immune challenge is dependent on successful preservation of naïve T cell repertoire. Age-associated erosion of naïve T cell pool may contribute to the decreased effectiveness of vaccines in older individuals.
Conditional ablation of H-2Kb and H-2Db on discrete APC subsets modulate outcomes in experimental cerebral malaria
Authors: Fain Cori E. , Rana Sabhya , Huggins Matthew A , Malo Courtney , Sieck Gary C. , Johnson Aaron J 
Published: January 2023

Abstract
Cerebral malaria (CM) is a severe complication arising from Plasmodium falciparum infection which results in high mortality. Lack of mechanistic insight into this pathology has resulted in ineffective therapeutic strategies. Using the Plasmodium berghei ANKA model of experimental cerebral malaria (ECM) our lab recapitulated hallmarks of human CM using small animal imaging, including blood-brain barrier (BBB) permeability, severe edema and microhemorrhage visible via T1 and T2-weighted MRI. Previously it had been demonstrated that infiltration of CD8 T cells with cytotoxic capacity is required to induce BBB permeability and ECM. The observation that not only infiltration, but cytotoxic killing is required provoked us to analyze differential MHC class I-restricted priming among discrete antigen presenting cell (APC) types. Using new MHC class I conditional knockout mice generated by our team, we addressed CD8 T cell priming and capacity to disrupt the BBB in ECM. Our findings revealed that mice lacking the H-2Kb MHC class I molecule expression in CD11c+ cells, but not LysM+ cells, were protected from the development of lethal ECM. Subsequently, conditional ablation of the H-2Db on these same subsets yielded similar results. Therefore, we demonstrate that both Db and Kb class I molecule expression by CD11c+ cells enable CD8 T cell priming that results in BBB permeability during ECM. In contrast, CD8 T cells primed by H-2Kb or H-2Db expressing LysM+ APCs are not capable of inducing BBB disruption. These results imply discrete APC subsets prime functionally distinct CD8 T cell responses in the CNS and modulate the outcome of cerebral malaria. This work begins to bridge the mechanistic gap and will impact future therapeutic strategies.
Deeper comparison of the human and mouse microbiota reveals the utility of mouse models
Authors: Beresford-Jones Benjamin Samuel , Kumar Nitin , Stares Mark , Vervier Kevin , Lawley Trevor , Pedicord Virginia Ahn 
Published: January 2023

Abstract
Mouse models are the backbone of many immunological studies and understanding their relevance to human disease is critical when interpreting results and moving research into the clinic. The intestinal microbiota performs essential roles in host physiology including immune development and metabolic encoding. However, it is currently uncertain to what degree the microbiota of mice is taxonomically and functionally comparable to humans. In addition, the microbiota has been identified as a leading cause of irreproducibility in mouse models but current mouse commensal genome databases are inadequate to define the microbes responsible. Better characterization of the mouse microbiota is therefore necessary to understand the relevance of mouse studies to human medicine, as well as produce cleaner, more reproducible science.
We performed high-throughput culturing and whole-genome sequencing of commensals from the faeces of specific pathogen-free mice. These genomes represent hundreds of novel species with which we define the taxonomic and functional relatedness of the mouse and human microbiota. We highlight functional pathways that are common and unique to each host species, thus describing areas of study where mouse models may be used validly. We also demonstrate the requirement for mouse commensal-specific databases for analysis of mouse samples.
Our work brings a new level of understanding to the mouse microbiota. By supplying an extensive selection of mouse commensal genomes, we facilitate comparison of the microbiota of mice, not only providing a means to understand issues of irreproducibility in mouse research but also delivering new opportunities to correlate and validate specific commensals with phenotypes of interest.