bluuebunny/crossref_metadata_2025_split huggingface dataset:
Using anti-CD38 immunotherapy to enhance anti-tumor T-cell immunity in chronic lymphocytic leukemia (CLL)
Authors: Manna Alak , Lewis-Tuffin Laura J. , Ailawadhi Sikander , Chanan-Khan Asher A. , Paulus Aneel 
Published: January 2023

Abstract
Increased CD38 expression on chronic lymphocytic leukemia (CLL) cells correlates with a negative prognosis, however, its utility as a therapeutic target in this malignancy remains unknown. Our investigations show that the anti-CD38 therapeutic mAb, daratumumab (Dara) induces direct apoptosis of CLL cells and promotes their immune-mediated clearance (through ADCC). Notably, CD38 expression is quite high on a subset of CLL-cells (CD19+/CD38hi/CD24+/IL-10+; B-regulatory-like phenotype), which promote Treg expansion while prohibiting CD8+ cytotoxic T-cells (cTLs). Indeed, immunosuppression is a hallmark of CLL and patients often present with increased number of Tregs and Th2 cells but decreased effector T cells and cTLs. It has recently been reported that CD38hi Tregs are significantly immunosuppressive and when examining this population in peripheral blood mononuclear cells (PBMCs) from CLL patients (n=13), we noted that &gt;50% of CD4+/CD25+/FoxP3+ cells were CD38hi (median MFI ~600). We hypothesized that Dara would kill CD38hi CLL cells à decreased CD38hi Treg formation/direct killing à expansion of cTLs. Indeed, ex-vivo treatment of CLL-patient derived PBMCs showed that Dara was highly lethal to both CD38hi “Breg-like” CLL cells and Tregs; associated with decrease in IL-10, increase in IFN-γ, effector T cells, Th17 subsets and proliferation of cTLs. Altogether this pointed towards recovery of anti-tumor immunity which was further evidenced by enhanced tumor-specific cytolytic activity of cTLs. Our pre-clinical data demonstrates that targeting CD38 in CLL has an anti-tumor effect via 1.) lethal effect on CLL-Bregs and Tregs and 2.) tumor-specific expansion of cTLs, which we will test clinically in an upcoming trial.
Intrapulmonary delivery of TLR agonists associated with systemic chemotherapy to treat metastatic cancer.
Authors: Goguet Emilie , Klinman Dennis M. , Tross Debra 
Published: January 2023

Abstract

Introduction
TLR7/8 agonist (3M-052) and TLR9 agonist (CpG ODN) both trigger innate immune responses supporting the induction of tumor-specific immunity. Previous studies showed that this specific combination of TLR agonists synergistically promoted the elimination of large established tumors (&gt;500 mm3). This effect was optimized when delivered directly into the tumor, leading to a conversion from immunosuppressive to inflammatory milieu. The current work explores the effect of a combination of a localized TLR agonists therapy and a systemic chemotherapy on lung metastases.

Methods
66Cl4-luc cells (a luciferase-expressing variant of the 4T1 murine mammary carcinoma line) were orthotopically implanted into the fourth mammary fat pad of syngeneic Balb/c mice. The combination therapy was initiated when the primary tumor exceeded 300 mm3 and pulmonary metastases were present.

Results
Treatment delivered into both the primary tumor and the lungs, when associated with systemic chemotherapy significantly reduced tumor growth and prolonged survival.

Discussion
The combined effect of the two TLR agonists was further enhanced when associated with classic chemotherapy, providing a significant decrease of tumor growth at both sites. These results provide new leads to explore when considering lung metastases treatment.
Investigating the effect of pegylated granulocyte colony stimulating factor therapy on experimental mastitis in lactating Holsteins
Authors: Powell Ellis J. , Lippolis John D. , Reinhardt Tim A. , Casas Eduardo 
Published: January 2023

Abstract
Mastitis dominates dairy economic and health concerns. Neutrophils are the most prominent cellular defense against mastitis causing pathogens making neutrophil expansion and activation, prime candidates for targeted therapeutics. The granulocyte colony-stimulating factor (gCSF) cytokine targets neutrophil differentiation and causes neutrophilia. Recently pegylated (PEG) gCSF has been shown to decrease naturally-occurring cases of mastitis. To better understand the mechanisms employed by PEG-gCSF to reduces mastitis incidence we have evaluated PEG-gCSF in an experimental mastitis challenge. We challenged 11 lactating Holsteins with Escherichia coli by intra-mammary infusion. Cows received injections of PEG-gCSF 14 days and 7 days, prior to disease challenge. While somatic cell counts in the milk did not differ between treated and non-treated animals, the treated cows had lower bacterial counts in the 48 hours post infection (P &lt; 0.05). Bovine serum albumin levels in milk, a measure of disease severity, were also lower 24 hours post challenge for PEG-gCSF treated animals. Post challenge, control cattle had reduced milk yield (P = 0.05) and a lower percent feed intake (P &lt; 0.01) compared to treated cows. PEG-gCSF treated cattle significantly increased circulating levels of neutrophils (P &lt; 0.01), as well as monocyte and lymphocyte responses (P &lt; 0.05). We demonstrated that PEG-gCSF treated cattle had reduced disease severity and have begun to further elucidate the mechanism of neutrophil immune responses. This data suggests the utilization of PEG-gCSF as a potential antibiotic alternative to mastitis treatment and prevention and supports neutrophil focused therapies as an important facet of mastitis disease protection.
Characterization of the cellular immune response to Brucella abortus RB51 vaccination and boost in cattle
Authors: Boggiatto Paola M. , Olsen Steven C. 
Published: January 2023

Abstract
Brucellosis is a bacterial zoonosis caused by organisms belonging to the genus Brucella. In domestic species (cattle, goats, sheep) brucellosis results in infertility and reproductive loss, while in humans, brucellosis results in a chronic debilitating disease. Worldwide, brucellosis is a significant source of financial loss and a major public health concern. Bovine brucellosis, as caused primarily by Brucella abortus, is an economically important cause of reproductive loss in cattle. While vaccines are available for cattle, safe and effective vaccines for humans (and other domestic species) are not available. Currently, most of the knowledge regarding protective immune responses against Brucella have come from mouse studies. In the work presented our goal was to characterize the T cell subpopulations and effector phenotype of the immune response elicited following vaccination and boost with RB51. In order to accomplish this, we performed ex vivo analysis of peripheral blood mononuclear cells (PBMC) for the expression of surface markers associated with effector (CD45RO− CD62L−/lo CCR7−) and memory phenotypes (TEM: CD45RO+ CD62Llo/intCCR7−and TCM: CD45RO+ CD62L+ CCR7+). Additionally, we performed in vitro recall responses of PBMC and assessed cytokine production and proliferation in response to antigen stimulation. Altogether, the data from these studies will help us understand the protective, cell mediated immune response elicited by vaccination in a natural host for Brucella species.
TCR Vbeta usage differences are associated with Marek’s disease resistance in the chicken.
Authors: Hearn Cari J. , Ray Emmillie , Cheng Hans H. 
Published: January 2023

Abstract
Marek’s disease (MD) is a herpesvirus-induced lymphoma in chickens which is of prime importance to the poultry industry, costing over $1 billion annually. Although vaccination controls the disease, virulence shifts have prompted efforts to improve genetic resistance in the host. We studied T cell responses in two models of MD resistance in inbred layer chicken lines. The first model is MHC-matched lines which have been selected for resistance (Line 6) or susceptibility (Line 7). The second model involves MHC-congenic lines which differ in MHC alleles known to be associated with higher (Line B21) or lower (Line B19) MD resistance. We characterized the usage of Vbeta-1+ and Vbeta-2+ TCRs in the T cell populations of birds infected and uninfected with Marek’s disease virus (MDV). Vbeta-1 and Vbeta-2 are the only two Vbeta gene families present in the chicken TCR loci, and are highly homologous within family. We found that resistant lines had a higher proportion of spleen T cells expressing Vbeta-1+ TCRs than susceptible lines, and that responses to infection were visible as shifts toward increased usage of Vbeta-1+ TCRs in CD8+, but not CD4+, T cell populations. While differences between MHC-congenic lines were small, resistant Line 6 showed a significant Vbeta-1+ CD8+ response as early as 8 days post infection, while susceptible Line 7 did not. We then characterized a panel of 6C.7 recombinant congenic lines, finding that TCR usage is most likely a single-locus trait, but interacts with other loci to produce a larger Vbeta-1+ T cell pool in more MD-resistant lines. We hypothesize that the reduced receptor diversity in the chicken may have led to strong selection effects on TCR-antigen-MHC fit which impact resistance to MDV infection or tumorigenesis.
Dendritic cells influence the altered neonatal CD8 T cell immunodominance hierarchy during influenza virus infection
Authors: Heil Luke , Oliphant Samantha , Lines Louise , Hollifield Melissa , Garvy Beth A. 
Published: January 2023

Abstract
Neonates are more susceptible to influenza virus infection than adults, resulting in increased morbidity and mortality as well as delayed clearance of the virus. Previous work has indicated that decreased T cell and dendritic cell function underlies some of this vulnerability. We sought to understand CD8 T cell specificity and immunodominance during neonatal influenza infection as well as how any differences from the adult hierarchy might impact immunodominance and protection in subsequent infections. We found that neonatal C57BL/6 mice display an altered CD8 T cell immunodominance hierarchy, preferentially responding to an epitope in the influenza protein PA rather than the co-dominant adult response to NP and PA. Additionally, upon secondary infection, mice first infected as pups display inconsistent immunodominance and suffer increased morbidity compared to mice infected previously as adults. Finally, transfer of influenza infected adult dendritic cells to pups resulted in increased T cell activation and enhanced viral clearance as well as a slight induction of NP specific CD8 T cells. Taken together, these data suggest that infection early in life alters the specificity of memory responses to that pathogen and that dendritic cells may play a role in mediating this process. Additionally, vaccines targeting T cells should consider epitope usage and age specific dendritic cell physiology if the intended patient population includes infants as well as adults.
Virus antigen-specific CD8 T cells contribute to brain atrophy during Theiler’s murine encephalomyelitis virus (TMEV) infection of the CNS.
Authors: Mix Madison R. , Ruiz Vanessa Y. , Huseby Kelcher April M. , Macura Slobodan I. , Mishra Prasanna K. , Johnson Aaron J. 
Published: January 2023

Abstract
Brain atrophy is a central feature of numerous neurological diseases for which the contribution of immune cells remains poorly defined. For example, in human multiple sclerosis, clonally expanded CD8 T cells have been observed in proximity to lesions, but their role in mediating brain atrophy has yet to be elucidated. This study aims to define how antigen-specific CD8 T cells contribute to brain atrophy in the TMEV model of neuroinflammation. Specific MHC class I haplotypes have been shown to dictate neuropathology and functional outcomes in mice following intracranial infection with TMEV. In this study, we demonstrate that transgenic FVB mice which express the H-2Db class I molecule rapidly clear picornavirus infection but at the cost of a novel neurodegenerative phenotype consistent with brain atrophy. Following TMEV infection out to four months, FVB mice expressing the Db class I molecule display increased lateral ventricular volume via T2-weighted MRI and hippocampal neuron loss by hematoxylin and eosin staining. Furthermore, these transgenic FVB mice present enhanced brain infiltration of virus-specific CD8 T cells for the immunodominant Db:VP2121–130 epitope. To address these findings mechanistically, we inhibited the Db:VP2121–130 epitope-specific CD8 T cell response and monitored the effect on brain atrophy. This inhibition strategy resulted in a reduction in brain atrophy to levels comparable to wild-type FVB controls. Not confounded by persistent infection or demyelination, these studies are the first to demonstrate antigen-specific CD8 T cells have the capacity to induce brain atrophy in a murine model of neurodegeneration.
Vitamin A deficiency provokes aberrant T cell responses and exacerbates liver injury in LCMV-infected mice
Authors: Liang Yuejin , Yi Panpan , Sun Jiaren 
Published: January 2023

Abstract
Vitamin A deficiency (VAD) is a public health problem worldwide; however, its role and underlying mechanisms in viral infection are not entirely understood. In this study, we detected elevated LCMV-specific T cell responses in VAD mice at the acute stage (7 dpi). These VAD mice exhibited higher serum ALT levels and increased liver permeability. Consistently, enhanced antiviral T cell responses were observed in VAD mice in persistent infection (30 dpi), as evidenced by decreased PD-1 expression and increased cytokine production. To investigate whether VAD causes an intrinsic abnormality of T cells during animal development and growth, we transferred spleen cells from control and VAD mice into CD45.1 recipient mice, followed by LCMV infection, and found that antiviral T cell responses were comparable between control and VAD donor cells. However, when CD45.1 cells were transferred into control and VAD recipient mice, they showed a highly activated phenotype in VAD mice. These results suggest that vitamin A or its metabolites restrict T cell activation through an extrinsic way. Retinoic acid (RA) is considered one of the important metabolites of vitamin A. We found that RA administration inhibited excessive T cell responses in VAD mice. To dissect the mechanism of RA, we treated splenocytes and purified CD8+ T cells with RA, followed by PMA stimulation. RA treatment reduced the phosphorylation of AKT, p38, ERK, and S6, as well as the abundance of transcriptional factor NFATc1. Together, our study demonstrated that VAD caused an aberrant T cell response to viral infection, and RA may have the potential to serve as a therapeutic agent for excessive immune responses and tissue injury in VAD patients.
A Random Forest based approach to MHC class I epitope prediction and analysis
Authors: Wilson Eric A. , Krishna Sri , Anderson Karen S. 
Published: January 2023

Abstract

Background
Increased hydrophobicity of the contact regions between MHC class I-restricted peptides and TCR is associated with increased immunogenicity. To improve prediction of antigenic peptides and to identify additional biochemical properties associated with immunogenicity, we have created a random forest (RF)-based computational model that evaluates target epitopes using 66 parameters that cover a range of amino acid biochemical properties.

Method
A dataset of publicly available 9 mer epitopes with experimentally defined immunogenicity (n=29,874) and/or HLA binding (n=108,069) were collected from IEDB and the MassIVE database. Epitopes restricted to target HLA alleles were scored based on the biochemical parameters of each amino acid, and used to train a RF model specific to that HLA. For biochemical property analysis, redundant features were removed with a wrapper algorithm before being used to train the RF model.

Results
The RF model specific for HLA-A*02:01 (n=5500) was evaluated for HLA binding and immunogenicity prediction accuracy using a mutually-exclusive testing set of HLA-restricted peptides that were non-immunogenic, immunogenic, or non-binders. The model showed an immunogenicity prediction accuracy of 83% with an AUC of 0.88, and a HLA binding prediction accuracy of 97.4%, with a sensitivity of 95.2% and specificity of 99.9%. The RF model confirmed that hydrophobic interactions at peptide positions 4 and 8 as well as H-bonding at position 1 were important for immunogenicity.

Conclusion
RF-based algorithms can be used to identify biochemical parameters associated with immunogenic class I-restricted T cell epitopes. This model is being expanded to other HLA alleles.
A role for the nonclassical MHC molecule DO in Treg selection and function
Authors: Jurewicz Mollie M. , Nanaware Padma Pandurang , Stern Lawrence J. 
Published: January 2023

Abstract
Selection of CD4 T cells into the conventional and regulatory lineages is thought to be dependent on the strength of interaction of rearranged T cell receptors with MHCII-bound peptides displayed on APCs in the thymus. The nonclassical MHC molecule DO inhibits DM-mediated peptide exchange and has been shown to play a role in selection of peptides for presentation to CD4 T cells. In mice deficient in DO (H2-O), alterations in T cell responses and in antigen presentation as well as increased autoimmunity have been described. We show that DO−/− mice have increased numbers of thymic and peripheral Tregs, which also display a more activated phenotype. These DO−/− Tregs additionally exert greater suppressive capacity in vivo as compared to WT Tregs, as demonstrated by reduced T cell activation following Treg transfer into Treg-deficient mice. T cell receptor Vβ chain sequencing indicates the Treg population is less diverse and the conventional CD4 T cell population more diverse in DO−/− mice, suggesting skewing of thymic selection as a result of DO expression. To understand the mechanism behind altered T cell selection due to DO, we eluted peptides from thymic and B cell-derived I-Ab and characterized them by tandem mass spectrometry. Peptide diversity was increased in both cell types isolated from WT as compared to DO−/− mice. We speculate that through control of peptide diversity, DO tunes the number and specificity of thymocytes selected into the Treg lineage. These results highlight a previously unappreciated role for DO in controlling Treg selection and function.
Identification of a gamma IFN inducible lysosomal thiol reductase (GILT)-dependent MHC-II associated epitope that induces T cell responses in GILT−/− mice
Authors: He Xiao , Reyes-Vargas Eduardo , Hu Dai , Wang Xiaomin , Jensen Peter E. 
Published: January 2023

Abstract
Gamma-IFN inducible lysosomal thiol reductase (GILT) is currently the only identified thiol reductase that has optimal activity at acidic pH and localizes to lysosomes. GILT is constitutively expressed in antigen presenting cells (APC), is inducible by gamma-IFN, and participates in Ag processing by catalyzing the reduction of disulfide (S-S) bonds, thus facilitating the unfolding of native S-S bond containing Ag for further processing. Previous studies reported that T cells from GILT knock-out (GILT−/−) mice mounted a significantly reduced proliferative response to S-S containing protein Ag in vitro, GILT−/− APCs have a selective deficiency in presentation of some cysteine-containing epitopes from hen egg lysozyme, and GILT−/− mice exhibited a change in the pathogenic epitope of experimental autoimmune encephalomyelitis. Using MS/MS analysis, we identified a set of unique GILT-dependent, MHC-II associated-peptides in WT vs. GILT−/− mice, which we then validate by generating T cells specific to a unique GILT-dependent epitope from GILT−/− but not WT B6 mice. Our data suggests that GILT−/− mice are deficient in the generation of specific T cell epitopes due to a loss in GILT activity. This is consistent with our another on-going study where we find that GILT−/− mice failed to generate an Ab response to insulin due to inefficient processing of an S-S containing epitope in insulin. We hypothesize that in GILT−/− mice, GILT inactivation causes a change in the epitope repertoire that may lead to survival (escape from negative selection) of the T cells specific to GILT dependent epitopes in the thymus. The presence of these auto-reactive T cells might have implications for autoimmunity and autoimmune diseases.
Assessing non-classical antigen presentation in HIV-infected CD4+ T cells.
Authors: Sengupta Srona , Boronina Tatiana , Cole Robert N. , Siliciano Robert F. , Sadegh-Nasseri Scheherazade 
Published: January 2023

Abstract
CD4+T cells recognize peptides presented by MHC Class II (MHC-II) molecules on B cells, dendritic cells, and macrophages. Interestingly, in humans, activated CD4+ T cells themselves express MHC-II molecules (HLA-DR, -DP, -DQ), but their potential role as antigen processing cells has not been well characterized. Recent promising data in a simian immunodeficiency (SIV) model suggest that antigen presentation by CD4+ T cells may be important in immunity. In these studies, a vaccine incorporating SIV antigens into a cytomegalovirus vector induced MHC-II restricted CD8+ T cells in macaques. Notably, these non-canonical cells were also observed in HIV patients. Clones generated from these MHC-II restricted CD8+ T cells killed autologous HIV-infected CD4+ T cells, suggesting that HIV is processed and presented on MHC-II on CD4+ T cells. To investigate this potentially novel form of antigen presentation, we eluted peptides from HLA-DR on activated CD4+T cells and sequenced them by LC-MS/MS. We show for the first time that human primary CD4+ T cells indeed process and present peptides on HLA-DR. We are currently applying this approach to HIV-infected cells to detect HIV peptides. Given the low sensitivity of untargeted MS for rare viral peptides, we are also generating a library of MHC-II HIV epitopes presented on HLA-DR to help guide more targeted MS analysis. To create this library, we are using a MHC-II cell-free processing system. We have already identified several epitopes from HIV Gag, Pol, Env, Vif, Rev, and Tat, some of which we show elicit memory responses in HIV patients. Our studies reveal a novel role for CD4+ T cells in antigen presentation and show that a cell-free processing system can predict HIV epitopes that may be presented on these cells.
The role of microRNA-22 in the dysregulation of lupus Tregs and the pathogenesis of systemic lupus erythematosus
Authors: Appleton Brenna , Faust Ashley W , Michell Danielle L , Ormseth Michelle J , Vickers Kasey C , Major Amy S 
Published: January 2023

Abstract
Systemic lupus erythematosus (SLE) is an autoimmune disease affecting over 1.5 million Americans and at least 5 million individuals worldwide. Evidence demonstrates autoantibody producing B cells and dysfunctional CD4+T cells contribute to SLE pathology, however lack of understanding surrounding mechanisms of disease pathogenesis have prevented therapeutic advancement. Studies indicate one mechanism for dysregulated immune homeostasis in autoimmunity is through microRNAs (miRNAs). MiRNAs are short, endogenous post-transcriptional regulators of gene expression which act by degradation or translation repression of target mRNAs. Our group previously identified miR-22-3p as being increased three-fold in SLE patient plasma compared to age- and gender-matched heathy controls. MiR-22-3p levels were increased in whole CD4+T cells (four-fold) and Tregs (three-fold) from B6.SLE1.2.3 mice compared to B6 controls, and inhibition of miR-22-3p, using locked-nucleic acid (LNA)-22 ameliorated key disease pathologies including glomerulonephritis. There was also a 10% reduction in IFN-g+CD4+T cells in mice treated with LNA-22. Based on these data, we hypothesized increased miR-22-3p levels in SLE T cells propagated inflammation directly by skewing naïve CD4+T cells towards the Th1 phenotype during polarization, or indirectly by reducing the regulatory capacity of Tregs. Results show miR-22-3p deficiency is not sufficient to prevent the polarization of Th1 cells. However, inhibition of miR-22-3p in vivo increases Treg IL-10 production, suggesting heightened levels of miR-22-3p may alter their function. We conclude that miR-22-3p overexpression in Tregs indirectly contributes to autoimmune T cell dysregulation in SLE.