bluuebunny/crossref_metadata_2025_split huggingface dataset:
Non-steroidal anti-inflammatory drugs reduce optimal antibody production in response to vaccination and vaccinia virus infection (45.18)
Authors: Phipps Richard , Bancos Simona , Topham David , Bernard Matthew 
Published: January 2023

Abstract
Protective humoral immune responses generated by vaccination, depends on optimal production of antibodies. Non-steroidal anti-inflammatory drugs (NSAIDs) are used to curb undesirable effects of vaccination such as fever. We previously demonstrated that B cells express the “proinflammatory” enzyme cyclooxygenase-2 (Cox-2) in response to activation stimuli such as the TLR9 ligand CpG DNA. Using genetic approaches and small molecule Cox-2 selective inhibitors, we demonstrated that Cox-2 is crucial for optimal antibody production. Expression of plasma cell transcriptional regulatory factors, including Blimp-1 and Xbp-1, were dependent on Cox-2 activity. Significantly fewer antibody secreting plasma cell precursors were generated in the presence of Cox-2 inhibitors, indicating that Cox-2 is essential for human B cell terminal differentiation. Mice chronically treated with Cox-2 inhibitors produced less neutralizing IgG following live virus infection with vaccinia virus. In vitro studies using human B cells show that all commonly used NSAIDs, as well as Tylenol (acetaminophen), at pharmacologic doses, blunt antibody production. Interestingly, a recent clinical trial showed that Tylenol use in infants blunted antibody responses to a variety of vaccines. These new data support the concept that the Cox pathway is necessary for optimal antibody production. The use of NSAIDs, may impair antibody production to vaccination and to certain infections.
Plasticity and commitment of memory CD8+ T cell progenitors early after infection (46.13)
Authors: Plumlee Courtney , Obar Joshua , Lefrancois Leo 
Published: January 2023

Abstract
Naïve antigen specific CD8+ T cells expand in response to antigenic stimulation to form a large effector T cell population. Following expansion, the majority of the antigen specific CD8+ T cells die, leaving behind a memory population capable of protecting the host. CD8+ T cell memory formation has been extensively studied, but little is understood about the early events in memory commitment. At the peak of the T cell response, effector T cells can be separated using the markers CD127 (IL-7Rα) and KLRG1. Memory precursor effector cells (MPECs) express CD127 while short-lived effector cells (SLECs) express KLRG1. CD8+ T cells lacking expression of both markers are called early effector cells (EECs) and can give rise to both the MPECs and SLECs. To understand if EEC populations are committed to either an MPEC or SLEC fate prior to differentiation, we used EECs generated from Listeria monocytogenes and vesicular stomatitis virus infections, where the ratio of SLECs/MPECs at the peak of the T cell response is known to be different. EECs were sorted and transferred into infection-matched or mismatched hosts at various days post infection. As late as 7 days post-infection the EECs were not committed to an MPEC or SLEC fate and could be driven in either direction based on the inflammatory environment of the host. Based on these results we conclude that commitment of a CD8 T cell toward a memory lineage does not occur until after CD127 expression has been established.
The priming stimulus dictates senescence of memory T cells (46.15)
Authors: Prlic Martin , Bevan Michael 
Published: January 2023

Abstract
Immunization drives the proliferation and differentiation of effector CD8 T cells followed by a contraction phase after the peak of the T cell response. The survivors of this contraction phase differentiate into long-lived memory cells, which can provide life-long protection. Generating long lived T cell memory through vaccination holds great promise to provide protection in situations where antibody-inducing vaccines fail. Prime-boost strategies have been used to repeatedly stimulate T cells with the aim of increasing memory T cell frequency. However, repeated stimulation of the memory T cell pool leads to T cell senescence and loss of responsiveness. We sought to determine whether a prime-boost vaccination strategy can be developed that does not suffer from this drawback. We report that the extent of senescence at the memory stage is determined during the primary response. We developed a system that allows priming of CD8 T cells without acquisition of maximal effector function and show that the ensuing memory population is fully functional upon rechallenge. Importantly, these memory cells derived from minimal effector T cells have full access to non-lymphoid tissue and are less senescent upon rechallenge than memory cells that did acquire maximal effector markers and function during priming. Understanding how the nature of the priming stimulus shapes memory T cell differentiation allows situation dependent tailoring of vaccines to achieve maximal protection efficacy.
Genome wide association study identifies many novel susceptibility genes for illumne related skin complex diseases (47.11)
Authors: Sun Liangdan , Yang Sen , Zhang Xuejun 
Published: January 2023

Abstract
With the completion of HGP and HapMap, the genome wide association study (GWAS) has become feasible and been proven to be a very useful and efficient approach to identify the susceptibility genes for complex diseases as compared to previous method in terms of linkage study. Psoriasis, vitiligo,SLE and atopic dermatitis are common immune related skin complex diseases with unknown pathogenesis. To identify the susceptibility genes predispoing to these dieases in Chinese Han populations, we carried out a seris GWAS for psoriasis, vitiligo, SLE and atopic dermatitis in Chinese populations and identified many novel genetic factors influencing disease susceiptibilty as well as found the genetic heterogenetity of these complex diseases within different ethinic populations(Nat Genet 2009, 2010). Our reserach should provide novel insights into the disease pathoghensis and lay a solid fundation for further functional research.
Congenic mouse strains identify a novel gene for which allelic variation affects susceptibility to type 1 diabetes (47.9)
Authors: Tan Iris , Mackin Leanne , Wang Nancy , Papenfuss Anthony , Elso Colleen , Ashton Michelle , Quirk Fiona , Phipson Belinda , Bahlo Melanie , Speed Terence , Smyth Gordon , Morahan Grant , Brodnicki Thomas 
Published: January 2023

Abstract
Type 1 diabetes (T1D) is an autoimmune disease resulting from the complex interaction of multiple genetic and environmental factors. The nonobese diabetic (NOD) mouse has proven to be a useful model for investigating T1D susceptibility loci and their immunological effects upon disease progression. We have mapped a NOD diabetes susceptibility locus, termed Idd11, on chromosome 4 (Chr4). A panel of congenic NOD mouse strains, harbouring different C57BL/6 (B6, a diabetes-resistant strain)-derived intervals for Chr4, localized Idd11 to an ~7kb interval. Comparison of diabetes incidence and crossover breakpoints for these strains suggested that a haplotype for this locus underlies T1D susceptibility in NOD mice. Based on publicly available databases, the Idd11 haplotype is located within a predicted gene of unknown function (AK005651). Genomic characterization of AK005651 reveals that this novel gene encodes multiple splice isoforms and open-reading frames, none of which has homology with known proteins. Preliminary expression analysis also indicates that AK005651 is differentially expressed in tissues relevant to T1D, with NOD mice demonstrating altered splicing and reduced expression compared to diabetes-resistant strains. Ongoing studies aim to determine the effect of Idd11 / AK005651 on T1D pathogenesis.
Indirect stimulation of human Vγ2Vδ2 T cells through alterations in isoprenoid metabolism: implications for cancer immunotherapy (48.14)
Authors: Morita Craig , Sarikonda Ghanashyam , Puan Kia-Joo , Feng Ju , Giner José-Luis , Cao Rong , Oldfield Eric , Wang Hong 
Published: January 2023

Abstract
Human Vγ2Vδ2 T cells monitor isoprenoid metabolism by recognizing (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP), an intermediate in the foreign MEP pathway used by protozoa and bacteria, and isopentenyl pyrophosphate (IPP), an intermediate in the self mevalonate pathway. Synthetic bisphosphonates (BPH), used for cancer immunotherapy, and alkylamines indirectly stimulate Vγ2Vδ2 T cells by inhibiting self farnesyl diphosphate synthase (FDPS), thereby increasing IPP which is directly stimulatory. Here, we further characterize stimulation by these compounds, and define pathways used by new classes of compounds. Consistent with FDPS inhibition, stimulation of Vγ2Vδ2 cells by BPH and alkylamines was much more sensitive to upstream statin inhibition than stimulation by phosphoantigens or mitogens. However, the continuous presence of BPH or statins was toxic, blocking Vγ2Vδ2 T cell proliferation but not cytokine release. SiRNA downregulation of FDPS in APC increased IPP and rendered them stimulatory for Vγ2Vδ2 cells. SiRNAs downregulation of isopentenyl diphosphate isomerase functioned similarly, albeit less potently. New stimulatory compounds-mevalonate and the alcohol of HMBPP-may also stimulate indirectly, but required high statin doses for inhibition. The critical chemical feature of BPH is the amino moiety, since BPH lacking amino moieties acted as direct antigens. Thus, a variety of manipulations affecting isoprenoid metabolism lead to stimulation of Vγ2Vδ2 T cells.
Reduced redox-regulating thiol levels render effector memory like T cells obtained after repetitive TCR stimulation more susceptible to activation-induced cell death (48.17)
Authors: Al-Khami Amir , Norell Håkan , Kaur Navtej , Naga Osama , Dinkins De’Angelo , Kesarwani Pravin , Voelkel-Johnson Christina , Mukherji Bijay , Nishimura Michael , Mehrotra Shikhar 
Published: January 2023

Abstract
Human antigen-specific CD8+ T lymphocytes have a heterogeneous phenotype that includes functionally distinct populations. Ex vivo-expanded CD8+ T cells used for adoptive immunotherapy generally acquire an effector memory-like phenotype (TEM cells) and exhibit impaired in vivo persistence and anti-tumor efficacy. Our data show that TEM cells (CD62LloCCR7loCD45ROhi) obtained after repetitive T cell receptor (TCR) stimulation show increased sensitivity to activation-induced cell death (AICD) induced by cognate antigen re-exposure compared to cells with a central memory-like phenotype (TCM cells; CD62LhiCCR7hiCD45ROlo). Of interest, TEM cells have reduced intracellular glutathione levels compared to TCM cells. This decrease in key redox-regulating thiol proteins inversely correlated to the extent of T cell proliferation and coincided with a decrease in the antioxidant protein thioredoxin. It was also associated with lower expression of the anti-apoptotic proteins bcl2 and bclxl and higher frequency of the T cell exhaustion markers CD57 and Tim-3. Treatment of tumor-specific T cells with the thiol donor N-acetyl cysteine increased cellular thiols and rescued T cells from AICD, without impairing their function. These data suggest that T cell expansion after antigen encounter could affect CD8+ T cell quality by decreasing its antioxidant capacity. Increasing the antioxidant capacity may increase the persistence of T cells and has translational implications for immunotherapy.
TCR transduced CD4+ T cells exhibit a TH1 phenotype while inhibiting priming of naïve CD8+ T cells by peptide-loaded mature dendritic cells (48.19)
Authors: Lesher Aaron , Norell Håkan , da Palma Telma , Graves Michael , Mehrotra Shikhar , Nishimura Michael 
Published: January 2023

Abstract
Adoptive immunotherapy is a promising new treatment modality for patients with advanced malignancies. A key limitation to adoptive T cell transfer is generating sufficient numbers of tumor reactive T cells for patient treatment. We have developed the ability to engineer T cells with TCR genes to redirect the specificity of PBL-derived T cells. A novel population we can produce are MHC class I restricted CD4+ T cells. CD4+ T cells have been implicated in the priming and maintenance of the CD8+ T cell response, in addition to having cytolytic properties in experimental models. In this study, tyrosinase-reactive human CD4+ T cells were created by retroviral transduction using a CD8-independent T cell receptor. Tyrosinase-reactive gene-modifed CD4+ cells produced IFN-γ, GM-CSF, and IL-2 in an HLA-A2 restricted, antigen-specific manner. Following tumor antigen recognition in vitro, TCR-transduced CD4+ T cells upregulated secondary costimulatory molecules, including OX-40 and 4-1BB. Despite their type I phenotype, priming of CD8+ cells by MART-1-loaded dendritic cells was impaired by these TCR-transduced CD4+ cells. Therefore, simultaneous engraftment of genetically-engineered CD4+ and CD8+ effector T cells may inhibit tumor killing by suppressing both CD8+ T cell induction and maintenance.
High throughput sequencing identified specific T cells from breast cancer tissue and peripheral blood (48.37)
Authors: Han Jian , Wang Chunlin , Sanders Catherine , Yang Qunying , Byrne-Steele Miranda , Lu Chiungmei 
Published: January 2023

Abstract
Tumor specific antigens may trigger an immune response that leads to T lymphocytes infiltrating the tumor tissue. We have developed methods using high throughput sequencing technology to study the immune repertoire within a sample (Wang et al., PNAS 2010). Using this method, we studied a patient’s surgically removed breast cancer tissue, the nearby normal tissue, and sorted peripheral blood. Dominant T cell clones with specific CDR3 sequences were identified from the breast cancer tissue. The same clones were found expressed at high levels in the nearby normal tissue and peripheral CD8+ cells. The clones were also expressed at low levels in other subsets of T cells in peripheral blood. Peripheral blood was collected after lumpectomy and radiation therapy from the same patient and subsets of T cells were sequenced. The study demonstrated the capability to identify specific T cells associated with a patient’s cancer tissue. These specific T cells can serve as personalized biomarkers for prognosis, treatment evaluations and early detection of recurrent tumors. Identification of these cancer specific T cells also make it possible to design personalized treatment strategies.
TLR-4 dependence of COX-2 and VEGF in prostate cancer (48.38)
Authors: Priyadarshini Anjali , Singh Shrawan , Kakkar Nandita , Chakraborti Anuradha 
Published: January 2023

Abstract
Introduction-Cancer is a complex multifactorial disease with many players including TLR-4, COX-2 and VEGF associated with inflammation and angiogenesis. Though some information is there regarding their individual role in prostate cancer, but their interdependence in disease pathogenesis has not been well studied. This study was done to relate the expression of COX-2 and VEGF with the expression of TLR-4. Method-The expression study was done in pathogenic malignant and benign prostatic tissue (Prostate cancer and BPH) by RT-PCR. Further, study of dependence of VEGF and COX-2 expression on TLR-4 was done on Prostate Cancer cell line LNCaP which was stimulated with Lipopolysaccharide (LPS). Results- Expression of TLR-4 and COX-2 was found to be significantly high in cancer tissue (p&lt;0.05). Expression of COX-2 and VEGF was found to be enhanced by stimulation of TLR-4 by LPS. Conclusions- Since upregulation of COX-2 and VEGF in Prostate cancer has already been well documented, a better understanding of the underlying biological mechanism of this may unveil new targets for therapy in patients of Prostate Cancer.
Upregulation of cytolytic functions of human Vd2neg gd T lymphocytes through engagement of ILT2/CD85j expressed by tumor target cells. (48.5)
Authors: Bonneville Marc , Harly Christelle , Scotet Emmanuel 
Published: January 2023

Abstract
In human adults, the majority of peripheral blood gd T cells expresses T cell receptors (TCR) using the Vg9 and Vd2 chains and recognize small nonpeptidic phosphorylated antigens. In contrast, most tissue-derived gd T cells, which are located mainly in spleen and epithelia, preferentially use Vd1 or Vd3 chains paired with diverse Vg chains to form their TCR. Our knowledge about the antigenic specificity and costimulation requirements of human Vd2neg gd T cells remains limited. To address this, we characterized the specificity of a murine mAb (#256), screened for its ability to specifically inhibit cytolytic responses of several human Vd2neg gd T cell clones (such as the Vg8Vd3 T cell clone #73R9) against transformed B cells (e.g. B-LCLs and Burkitt’s lymphomas). Using gd#73R9-derived TCR transfectants and comparative gene expression arrays, we show that mAb#256 does not target a gdTCR ligand, but blocks a key activation pathway involving interaction between non-TCR molecules on effector gd T cells and ILT2 (LILRB1/CD85j) molecule, expressed by tumor targets. In line with the previously reported specificity of this NK receptor for classical and non-classical MHC-I molecules, blockade of MHCgd class I / ILT2 interactions using MHC I- or ILT2-specific mAbs and ILT2-Fc molecules, gdinhibited tumor-induced activation of Vg8Vd3 T cell clones. Therefore, this study describes a new CTL activation pathway involving MHC class I engagement on gd T cells.
Immunotherapy of pancreatic adenocarcinoma using adoptive cell transfer of redirected T lymphocytes (48.6)
Authors: Eshhar Zelig , Maliar Amit , Servais-Mavor Charlotte , Waks Tova 
Published: January 2023

Abstract
Pancreatic adenocarcinoma (PAC) is a common malignancy that is often diagnosed at an advanced stage, when surgery is not feasible. Here we investigated in an animal model whether adoptive cell transfer using redirected, tumor-specific T cells could be applied for the treatment of primary and metastatic PAC. To this end we genetically engineered. human effector T cells (‘T-bodies’) to express antibody-based chimeric receptor against pancreatic tumor markers CD24 (putatively defined as PAC stem cell antigen) or Her2/neu. In in-vitro co-culture studies we demonstrated that both CD24 and Her2/neu specific T-bodies were specifically stimulated and lysed PAC cells. In-vivo experiments showed that T-body treatment of SCID mice bearing Capan-1, PAC cell-line was highly effective in reducing tumor size and prolongation of survival. Moreover, in an orthotopic model, most mice systemically receiving human T-bodies, remained disease-free for several months whereas all control animals developed large tumors. Using luciferase-labeled PAC demonstrated that these treatments resulted in the elimination of metastases in the liver and draining lymph nodes. Repeated course of T-bodies resulted in complete responses in more than 50% of the treated mice. Intratumoral injection of T-bodies eliminated more than 80% of the tumors. Taking together, we suggest redirected lymphocytes as an efficient cell-therapy modality for systemic treatment of localized and disseminated pancreatic adenocarcinoma.
Cytokine expression pattern differences between conserved versus non-conserved influenza pandemic H1N1-specific CD4 T cells (49.15)
Authors: Weaver Jason , Deng Nan , Bishop Courtney , Mosmann Tim 
Published: January 2023

Abstract
The T cell response to conserved epitopes of influenza, which have been primed and repeatedly boosted in most adults, is a strongly biased Th1 response in which most responding cells produce TNFα, IFNγ and IL2. We have now analyzed the cytokine specificity of the T cell response to non-conserved peptides from the pandemic H1N1 influenza virus. This response should be enriched for non-cross-reactive responses that have been primed by a single exposure, but not boosted. Pepsets spanning the H1N1 proteome of a seasonal flu, pandemic flu, and vaccine components were sorted according to amino acid sequence comparisons into identical and non-identical groups. PBMC from healthy donors were stimulated with the different peptide pools and cytokine expression patterns were analyzed by flow cytometry. Peptides identical in all three strains or identical between the seasonal H1N1 and pandemic H1N1 induced responses biased toward expression of TNFα+IFNγ+IL2+/-. In contrast, the pool of peptides unique to the pandemic H1N1 induced more TNFα+IFNγ-IL2+ producing T cells. These data suggest that responses against unique peptides of H1N1 (some of which will be non-cross-reactive with other influenza strains) include relatively more IL2-producing cells, possibly including the IFNγ-IL2+ non-polarized (Thpp) cells that are typically induced by protein vaccination. These cells may be further polarized by repeated stimulation during subsequent infections.
Enhanced induction of CD4+CD25+FOXP3+ suppressive function in memory versus naïve CD4+CD25-FOXP3- T-cells is proportional to strength of activating stimulus. (50.2)
Authors: Mohiuddin Imran , Pillai Vinodh , Mendoza Jason , Lee Thomas , Karandikar Nitin 
Published: January 2023

Abstract
CD4+CD25+FOXP3+ regulatory T-cells (Tregs) play a vital role in suppressing autoimmune responses. We have previously shown that, in humans, all activated T-cells attain a state of transient FOXP3 expression that correlates with transient suppressive ability. In fact, peripheral generation of induced Tregs (iTregs) is likely the dominant source of regulatory cells in healthy adults. Through the use of a sensitive flow-based suppression assay, we observed that both memory and naïve CD4+CD25-FOXP3- T-cells developed regulatory ability following a variety of activating stimuli. This suppressive ability was not due to competition for nutrients or antigen presenting cells. Interestingly, memory T-cells displayed significantly greater FOXP3 induction compared to naïve counterparts, and this phenotype correlated to significantly enhanced suppressive function. Furthermore, acquisition of suppressive ability in both the memory and naïve iTreg compartments was proportional to the strength of activating stimulus. While blockade of activation using anti-IL-2, CTLA-4 Ig, anti-TGF-B, indomethacin or cyclosporin A did not affect iTreg generation, methotrexate drastically preempted the induction of regulatory ability. Moreover, irradiation of iTregs also abrogated regulatory function. These studies suggest that iTreg development and function may vary dependent on precursor origin and emphasize the importance of characterizing the iTreg compartment prior to therapeutic application.
Resveratrol and curcumin: effects on human T cells (50.7)
Authors: Valenzuela Hector , Molgora Brenda , Bateman Riley , Wu Jennifer , Sweeney Greg , Effros Rita 
Published: January 2023

Abstract
Various natural products have been proposed to both increase health at the organismic level, and delay the onset of cellular aging. Of particular interest is resveratrol, a phytoalexin that has been demonstrated to have cardioprotective effects and to slow the progression of a variety of illnesses, including various types of cancers. More recently, resveratrol has been demonstrated to increase the maximum lifespan of model organisms, such as C. elegans, D. melanogaster and N. furzeri. However, the potential health benefits of resveratrol and other similar compounds on the human immune response have not been adequately addressed. We have, therefore, initiated research to determine the in vitro effects of the nutraceuticals resveratrol, and its analogs (polydatin and acetyl-resveratrol), as well as curcumin on a variety of human T cell functions. In this study we evaluated the effect of these compounds on proliferative potential, telomerase activity, expression of costimulatory and memory surface markers and sirtuin gene expression profiles of both human CD4 and CD8 T cells. Our data show that these compounds stimulated strong dose-dependent anti-inflammatory responses, and upregulated surface protein markers associated with the suppression of T cell activity. Our preliminary results suggest that these compounds may function to down-modulate ongoing CD4 and CD8 immune activity, while, nevertheless, poising the T cells for a subsequent immune response.