bluuebunny/crossref_metadata_2025_split huggingface dataset:
TIGIT mediates experimental ischemia reperfusion and nephrotoxic acute kidney injury in mice
Authors: Noel Sanjeev , Lee Kyungho , Gharaie Sepideh , Kurzhagen Johanna T , Arend Lois J , Kuchroo Vijay K , Cahan Patrick , Rabb Hamid 
Published: August 2023

Abstract

Background
We unexpectedly found upregulated expression of T cell immunoreceptor with Ig and ITIM domains (TIGIT) on kidney CD4 T cells after ischemia reperfusion (IR) using RNA-Seq. However, TIGIT role in kidney T cells and during acute kidney injury (AKI) is poorly understood.

Methods
Effect of TIGIT on murine kidney T cells was assessed at baseline and after IR injury by flow cytometry and single cell RNA sequencing (scRNA-Seq). B6 wild type (WT) and TIGIT knockout (KO) mice were subjected to IR and cisplatin-induced AKI. TIGIT expression was assessed in AKI patients using the Kidney Precision Medicine Project (KPMP) scRNA-Seq dataset.

Results
We found increased kidney CD4+TIGIT+ central memory (10.0±2.3 vs 0.9±0.1%, p=0.001) cells compared to CD4+TIGIT− cells in WT mice. TIGIT KO mice had reduced serum creatinine (SCr) after IR (24h Scr, 1.1±0.2 vs 2.7±0.1 mg/dL; p≤0.001) and cisplatin (72h Scr, 0.8±0.1 vs 1.4±0.1 mg/dL; p=0.0002) injury compared to WT mice. TIGIT KO kidneys had reduced necrotic tubules in outer medulla after IR (48.8±4.7% vs 73.0±1.5%; p=0.001) and cisplatin (11.5±3.0% vs 31.3±4.0%; p=0.008) injury than WT kidneys. Gene set enrichment analysis of scRNA-Seq data showed enrichment of inflammatory genes in Th17 cells from WT kidney and oxidative phosphorylation and mTORC1 signaling genes in TIGIT KO kidney. Human KPMP data demonstrated significant TIGIT expression in kidney T/NK cells from AKI patients compared to controls (p≤0.0001).

Conclusions
TIGIT mediates both IR and nephrotoxic AKI in mice and its expression increases in kidney T cells from AKI patients. TIGIT is a promising novel therapeutic target for AKI, and also relevant due to increasing efforts to develop TIGIT blockade to treat cancers.

American Society of Nephrology, Johns Hopkins University Ed Kraus Award, National Kidney Foundation of Maryland and Delaware
Inducing cell-intrinsic dysfunction in pregnancy-sensitized alloreactive B cells
Authors: Durgam Samarth S , Wang Qiang , Yin Dengping , Alegre Maria-Luisa , Chong Anita S 
Published: August 2023

Abstract

Objective
Pregnancy is an immunological paradox where the maternal immune system develops tolerance to semi-allogeneic fetus yet is a sensitizing event that is detrimental to subsequent organ transplantation. Humoral sensitization by semi-allogeneic pregnancy in WT mice prevents anti-CD154-mediated tolerance to fetus matched allograft. In contrast, pregnancy in mice lacking secreted immunoglobulins (mIgM−/−AID−/−; SIgKO) permitted anti-CD154 mediated transplant tolerance, suggesting that fetus-specific antibodies (FSA) were mediating resistance to anti-CD154. Here, we tested whether pregnancy-induced memory B cells could be desensitized to acquire a state of cell-intrinsic dysfunction.

Methods
Pregnancy-sensitized SIgKO or WT mice were subjected to fetus-matched heart transplant/anti-CD154 (PP-tolerant B) or not (PP-memory B). Enriched B cells were adoptively transferred (AdTr) into secondary hosts (MD4 mice) and challenged with fetus-matched splenocytes. Germinal center (GC) allo-reactive B cells from MD4 mice were identified with MHC tetramers, and Fas+GL7+.

Results
While SIgKO PP-memory B cells differentiated into GC-B cells in secondary hosts; this was significantly decreased by 7–10-fold in SIgKO PP-tolerant B cells. In contrast, WT PP-memory B cells and PP-tolerant B cells comparably differentiated into GC-B cells.

Conclusions
In the absence of FSA, PP memory B cells can acquire a cell-intrinsic hypo-functional state. This suggests possible B cell desensitization for multiparous women, who are currently disadvantaged by pregnancy-induced humoral sensitization.

R01AI42747, P01AI097113
Loss of autoreactive B cell tolerance and production of autoantibodies in chronic kidney allograft rejection in mice
Authors: Sayin Ismail , Oien Jacqueline , Ghosh Deepjyoti , Yin Dengping , Durkee Madeleine S , Sage Peter T , Clark Marcus R , Chong Anita S F 
Published: August 2023

Abstract
Loss of autoreactive B cell tolerance and production of autoantibodies have been observed in patients undergoing chronic rejection. However, how autoreactive B cells lose their tolerance, and the role of autoreactive antibodies in chronic rejection remains an enigma. Recent observations from our laboratory that autoreactive B cells with a transcriptome profile of innate B cells accumulate in transplanted kidneys diagnosed with antibody-mediated rejection led us to hypothesize that (i) the loss of autoreactive B cell tolerance occurs primarily in the inflamed kidney and (ii) autoantibodies are contributing to graft rejection. In this study, we developed acute and chronic mouse kidney transplant models to test these hypotheses. Donor-specific antibody responses were assayed using donor MHC coated multiplex beads. Autoantibodies were detected with Hep-2 autoantibody detection kit and quantified with an image analysis pipeline in CellProfiler. The presence of autoantibody secreting cells was confirmed by graft tissue culture, and accumulation of autoreactive B cells was confirmed by ex vivo Nojima cultures. We found that autoantibodies were produced during chronic and acute kidney allograft rejection, even when donor MHC-specific antibody was inhibited with CTLA-4Ig. Remarkably, autoantibodies specific for cytoplasmic, nuclear and nucleolar antigens dynamically changed over time, suggesting rapid epitope spreading. Furthermore, there was an enrichment of autoreactive B cells and autoantibody secreting cells in the graft. Taken together, our mouse models complement data from rejecting biopsies, demonstrating a loss of autoreactive B cell tolerance and accumulation of autoantibodies within rejecting allografts.
Supported by grant from NIH R01AI148705
Effects of temperature on success of scale autografts and allografts in Poecilia reticulata
Authors: Redmond Sarah , Aneli Kiana , Benson Aaliyah , Bridge Aidan , Brown David , Cardenas Andrew , Kennedy Jonah , Redden Alex , Spencer Sierra , Twum Analisa , Wolfe Miranda , Aguilar Marcella , Akers Ashanti , Alshami Duha , Christman Zach , Cruz Alex , Daniel Mark , Dean Sierra , Ennis Ashton , Rodriguez Stefani Guendulay , Harmon Tessa , Johnson Zach , Kravchick Rebecca , Krumtum Rachel , Locklear Abby , Martinez Jazmin , Matthews Chad , Mendola John , Rea Scout , Reed Cierra , Rose Austin , Rupert River , Simpkins Brooke , Sisk Katie , Smith Caleb , Swallow Austin , Tall Ilana , Tamanjah Mamata , Theo Kalina , Thomas-Todd I’adore , Wheeler Katie 
Published: August 2023

Abstract
Acceptance or rejection of transplanted tissues is dependent upon both genetic and environmental factors. We used guppy fish, Poecilia reticulata, as a model for studying those factors impacting the immune response to transplanted scale tissues. Scale tissue acceptance is observed when blood has begun to circulate throughout the grafted tissue and rejection can occur at different time intervals due to the degree of genetic difference between donor and recipient. Individual fish were genotyped for MHC class I (UBA) and MHC class II (DAA and DAB) similarity and underwent both autografts and genetically distinct allografts, followed by a recovery period with different environmental temperatures. Fish exhibit behavioral fever under infection and stress models, and were expected to show different levels of inflammation and graft success at different environmental temperatures. We set tank temperatures at 20, 23, and 26 degrees Celsius (n = 5 fish per tank) and monitored subjects for five weeks following the graft procedure to observe for signs of chronic rejection. Typically, chronic rejection takes two to three weeks to become evident, fish were monitored longer to confirm acceptance or rejection of the grafts. We observed signs of rejection, including necrosis and loss of pigmentation, at higher rates in allografts than in autografts.
The effects of microplastics on autografts and allografts in Poecilia reticulata
Authors: Redmond Sarah , Aneli Kiana , Benson Aaliyah , Bridge Aidan , Brown David , Cardenas Andrew , Kennedy Jonah , Redden Alex , Spencer Sierra , Twum Analisa , Wolfe Miranda , Aguilar Marcella , Akers Ashanti , Alshami Duha , Christman Zach , Cruz Alex , Daniel Mark , Dean Sierra , Ennis Ashton , Rodriguez Stefani Guendulay , Harmon Tessa , Johnson Zach , Kravchick Rebecca , Krumtum Rachel , Locklear Abby , Martinez Jazmin , Matthews Chad , Mendola John , Rea Scout , Reed Cierra , Rose Austin , Rupert River , Simpkins Brooke , Sisk Katie , Smith Caleb , Swallow Austin , Tall Ilana , Tamanjah Mamata , Theo Kalina , Thomas-Todd I’adore , Wheeler Katie 
Published: August 2023

Abstract
Over half of the microplastics found in the ocean are polystyrene - this impacts naturally harvested fish and shellfish in those environments. Recent studies have shown that, in fish, polystyrene microplastics affect growth, development, chemical responses, and digestive contents. Microplastics are not directly immunogenic, but can increase general inflammatory signaling due to tissue damage - fish are particularly sensitive to this type of damage because their respiratory and digestive systems are in constant interaction with the aquatic environment. This study addresses the effects of varying concentrations of polystyrene microplastics on the immune response to scale autografts and allografts in Poecilia reticulata (guppy fish). Tank conditions with microplastic concentrations of 0 particles/m3, 2,500 particles/m3, 10,000 particles/m3, and 80,000 particles/m3 were used to represent the range of natural environments with 4 fish per treatment group. Each individual fish underwent bilateral scale grafts, with autografts on one side and genetically distinct allografts on the other side. Genetic differences were confirmed based on genotyping the UBA locus - representative of MHC class I. Post-surgical graft monitoring used necrosis and pigment loss as markers of chronic rejection and vascular development as a marker of graft success. Chronic rejection based on genetic differences is observable in the differential success of autografted and allografted scale tissues.
Microbiota regulation of thymic microbiota-specific T cell development
Authors: Ruiz Daniel Fernando Zegarra , Chen Amanda , Acosta Monica , Kim Dasom V , Callaghan Ryann C , Saldana-Morales Fatima B , Matthews Dean , Stanford Nikketa , Longman Randy S , Bettini Matthew L , Diehl Gretchen E 
Published: August 2023

Abstract
While exposure to microbial antigens in peripheral sites causes expansion and differentiation of antigen-specific T cells, a role for antigen-specific expansion had not been identified during T cell development in the thymus. We recently found that intestinal colonization induced migration of dendritic cells carrying bacterial antigens to the thymus, driving thymic expansion of microbiota-specific T cells early in life. In contrast, colonization in adulthood led to expansion of peripheral but not thymic microbiota-specific T cells. Thymic microbiota-specific T cells expanded early in life could cause intestinal inflammation in colitis models upon antigen reencounter. We next sought to understand microbiota regulation of this developmental window and define if thymic expansion of microbiota-specific T cells could be restarted in adulthood. Remarkably, we found that microbiota manipulation reestablished expansion of microbiota-specific T cells in the adult thymus. In contrast to early life, adult thymic microbiota-specific T cells ameliorated intestinal inflammation in colitis models. In both early life and adulthood, development of thymic microbiota-specific T cells was driven by the same intestinal dendritic cell population. Our data suggests that intestinal colonization controls the development of thymic microbiota-specific T cells which can modulate inflammatory processes.
NIH (K99AR080207)
Bioengineering Advanced Artificial Antigen Presenting Cells for Immunotherapy
Authors: Shannon Sydney R , Hsieh Zoe , Green Jordan , Schneck Jonathan P 
Published: August 2023

Abstract
Promising cytotoxic (CD8+) T cell-based cancer therapies have invigorated recent efforts to develop highly tunable, robust, and cost-effective artificial antigen presenting cells (aAPCs) for T cell stimulation both ex vivo and in vivo. Natural APCs, such as dendritic cells (DCs), can be licensed to deliver optimal activation signals (peptide-MHC as S1, costimulatory S2, and cytokine S3) to CD8+ T cells with CD4+ T cell help. While numerous studies demonstrate that “un-helped” CD8+ T cells mount defective responses, many existing therapies overlook this and handicap the function/persistence of the resulting cells. The objective of this study is to synthesize a tri-signal aAPC that couples the CD4+ T cell/DC interaction to stimulate anti-tumor CD8+ T cells.
Using novel blends of poly(lactic-co-glycolic acid) (PLGA) and cationic poly(beta-amino-ester) (PBAE) polymers, we synthesized double emulsion microscale aAPCs containing S3 (murine IL-2) encapsulated into the particle core, with S1 (anti-CD3) and S2 (anti-CD28) conjugated to the particle surface. Dynamic Light Scattering measurements show particles of approximately 2 μm in diameter and conjugation efficiency assays showed similar amounts of bound S1 (0.858 μg protein/mg particles) and S2 (0.939 μg protein/mg particles). CD8+ T cell stimulation shows 20-fold proliferation when aAPCs are incubated with CD8+ T cells.
Thus, biodegradable PLGA/PBAE aAPCs can recapitulate natural immune cell interactions for optimal CD8+ T cell anti-cancer efficacy. Currently, we are characterizing additional aAPC physicochemical and biological properties. Our novel biomimetic aAPC has both translational relevance and may also shed light on basic T cell biology.
Intracellular Monitoring by Dendritic Cells – a New Way to Stay Informed – From Simple Scavenger to Active Gatherer
Authors: Herbst Christopher H , Bouteau Aurélie , Igyarto Botond Z 
Published: August 2023

Abstract
The ability of dendritic cells (DCs) to acquire antigen from their environment is critical for the induction of an adaptive immune response and the maintenance of tolerance. Despite its importance, it is tacitly assumed that DCs acquire antigen by scavenging extracellular material via endocytosis or macropinocytosis. Here, using labeled RNA and time lapse imaging, we observe DCs siphoning material directly from live neighboring keratinocytes. This contact dependent mechanism of antigen uptake – which we term intracellular monitoring – accounts for a large percentage of RNA transferred to DCs, and cannot be blocked by inhibitors of known antigen uptake processes. It is exclusive to DCs, as other cell types do not efficiently siphon RNA from neighboring cells, and common among most DCs subsets tested. Langerhans cells with a conditional gene deletion can successfully overcome their deficiency by siphoning RNA and protein from their neighbors, but only if the deleted protein is expressed in the donating cell. Such behavior reframes our understanding of DCs from mere scavengers to highly informed supervisors with extensive access to the cytosol of surrounding cells. Intracellular monitoring may therefore play important roles in the maintenance of tolerance, defense against infection, and detection of cancerous cells.
Visualization and characterization of the elusive MHC I intermediate states by x-ray crystallography and in silico studies
Authors: Bouvier Marlene , Peng Xubiao , Li Lenong 
Published: August 2023

Abstract

Background
Studies have suggested that MHC class I (MHC I) molecules fluctuate rapidly between conformational states as they sample peptides for potential ligands. It is the molecular features of these intermediates that are recognized by tapasin and TAPBPR at the C-terminus of the groove. To date, however, MHC I intermediates remain elusive molecules due to their transient nature. Moreover, whether the N-terminus of the groove has a role in MHC I maturation, and if it also serves as a conformationally sensing region, is not well characterized.

Methods
We designed the HLA-B8-restricted 20mer (RA)6FAKKKYCL and (RA)6FVKKKYCL peptides and corresponding 8mer FAKKKYCL and FVKKKYCL controls. We determined the x-ray crystal structures of HLA-B8E76C presenting these four peptides. Molecular dynamics (MD) simulations of the complexes were also performed.

Results
The structures of FA and FV 20mers revealed significant conformational heterogeneity at the N-terminus of the groove. Long stretches of N-terminal MHC I residues were missing in the electron density maps creating an unstructured and widely open-ended groove. Our structures also showed highly unusual features in MHC I and peptides at the N-terminus of the groove, and in MHC I-peptide interaction. MD simulations showed that these complexes have varying degrees of mobility in a manner consistent with our structures. We suggest that our 20mer structures represent conformational substates explored by MHC I during peptide selection.

Conclusion
Our study advances our understanding of peptide-induced conformational adaptation and functional dynamics in MHC I, and brings into focus the N-terminus of the groove as an important region in mechanisms of high-affinity peptide selection.

NIAID, National Institutes of Health (R01 AI114467, R01 AI108546, and R21 AI173863)
Characterization of the HLA-F ligandome in T-cell lymphoma
Authors: Mota Ines Frutuoso , Osean Jaspreet , Song Eric , Clement Cristina C , Lenz Jack , Miller Danny E , Inghirami Giorgio , Montagna Cristina , Bouvier Marlene , Iwasaki Akiko , Santambrogio Laura 
Published: August 2023

Abstract
Identifying tumor-specific antigens across different types of malignancies and HLA haplotypes remains challenging. Recently, the expression of tumor-specific Human Endogenous Retroelements emerged as a potential new class of cytotoxic T-cell response mediators (1). HLA-F, a non-classic HLA-I molecule, has been hypothesized to present peptides to T-cells and to regulate immunity through interactions with distinct NK-cell receptors (2). HLA-F low genetic diversity and limited peptide repertoire represent an unexplored avenue in cancer immunotherapy. HLA-F-bound peptides were eluted from five patient-derived T-cell lymphoma cell lines and total T-cells purified from ten healthy donor PBMCs; Retroelement peptides were identified in the HLA-F ligandome. To quantify and validate their expression, RNA-sequencing data from the same samples were screened using ERVmap database (3). Lastly, to characterize their expression, we incorporate genome-wide characterization of DNA methylation patterns. We identified a set of retroelement peptides bound to HLA-F shared by patient-derived T-cell lymphoma cell lines but not total T-cells isolated from healthy donor PBMCs, suggesting a potential role of HLA-F in cancer-immune responses. Among those we characterized four tumor-specific retroelement peptides, validated by the presence of their RNA transcripts as well as by DNA integration and chromosomal location. Tumor-specific HLA-F-bound retroelement peptides hold great promise for the discovery of previously unknown tumor-specific markers and therapeutic targets. More importantly, the characterization of their immunogenicity may yield insights broadly applicable to a greater number of patients due to HLA-F monomorphism.
mRNA-adjuvanted Influenza A Vaccine Can Induce High Cellular Immunity and Cross Reactivity in Mice
Authors: Wei Lai 
Published: August 2023

Abstract
In recent years, the great success of mRNA-based vaccines for SARS-CoV-2 revealed a potential future for safe and effective mRNA vaccine designs. Given the flexibility and accessibility of mRNA designs, adjuvants in mRNA forms may be applied to enhance immune response and generate better cross-protection. In this study, we fabricated an Influenza mRNA lipid nanoparticle (LNP) vaccine with Influenza A/Aichi/2/1968 (Aichi, H3N2) Hemagglutinin (HA) mRNA and cytokine-adjuvant mRNA (GIFT4 or CCL27). We found that two doses of immunization with mRNA-adjuvanted LNPs induced increased antigen-specific antibody titer and effective protection against Influenza A viruses in mice. The supplement of cytokine mRNAs (GIFT4 or CCL27) provided more robust immunogenicity, including more IL-4 and IFN-γ secreting T cells in the spleen and more IgG and IgA-secreting B cells in the bone marrow. The cytokine mRNA adjuvants also induced early activation of T and B cells in germinal centers. Thus, GIFT4 and CCL27 mRNAs are potential adjuvants for Influenza A mRNA vaccine to elicit higher and broader immune responses in mice.
Army Liposome Formulation Augments the Immunogenicity of HIV-1 AIDSVAX® B/E Protein
Authors: Kim Jiae , Allam Atef , Peachman Kristina K , Onkar Sayali , Matyas Gary R , Sinangil Faruk , Alving Carl R , Rao Mangala 
Published: August 2023

Abstract
Adjuvants play a critical role in activating innate cells, which can shape the subsequent adaptive immune response including the durability. The RV144 HIV-1 Vaccine Phase 3 Trial tested ALVAC® DNA (prime) and HIV-1 gp120 subtype B/subtype E (AIDSVAX® B/E) protein as the boost. Although, the vaccine regimen showed a modest 31.2% efficacy with antibodies to gp120 V1V2 region as one of the correlates of protection, the immune responses were not durable. Therefore, to enhance durability, we mixed AIDSVAX® B/E which contained aluminum hydroxide (AH) as the adjuvant with lyophilized Army Liposome Formulation containing monophosphoryl lipid A (MPLA; ALF). BALB/c mice were immunized 1, 2 or 3 times at 3-week intervals with AIDSVAX® gp120 B/E (AH adjuvant) or with AIDSVAX® gp120 B/E-ALF (AH and liposomal MPLA adjuvant; ALFA). Spleens were collected on days 3, 5 (after 1 or 2 immunizations), and week 10 (after 3 immunizations), and analyzed by flow cytometry for plasma cells (PC) and T follicular helper cells (Tfh). Serum samples were analyzed for antibody responses by ELISA. ALFA adjuvanted protein induced 2–8-fold higher antibody titers against gp120 V1V2 region at the time points tested compared to AH adjuvanted protein. ALFA induced a higher proportion of PC (B220−IgD−CD138+PNA−GL7−) and IL-21 producing Tfh cells as early as days 3, and 5. At week 10, PC and Memory Tfh cells (CD4+CD44hi CXCR5+PD-1hiBCL-6hi) were also increased in the ALFA group with a higher expression of the activation marker CD40 on germinal center B cells. Microarray analysis of splenic PCs showed increased expression of signaling pathways involved in PC proliferation and antibody secretion. These factors likely contributed to the robustness of ALFA as a vaccine adjuvant.