bluuebunny/crossref_metadata_2025_split huggingface dataset:
Elucidating the mechanisms of CD8 T cell plasticity (46.1)
Authors: Ceccato Christina , Durham Nicholas , Bruno Tullia , Nirschl Christopher , Tam Ada , Drake Charles 
Published: January 2023

Abstract
Christina M Ceccato, Nicholas Durham, Tullia Bruno, Christopher Nirschl, Ada Tam, Charles G Drake. When a naïve CD8 T cell encounters antigen, it acquires a cytokine secreting phenotype in addition to cytotoxic capacities. We and others have shown that CD8 cells cultured in the presence of IL-6 and TGFβ acquire the capacity to secrete IL-17 and lyse specific targets in vivo but not in vitro. We also demonstrated in vivo plasticity of the Tc17 phenotype by showing that adoptively transferred Tc17s convert from an IL-17 to an IFNγ secreting phenotype and are maintained in higher numbers than transferred Tc1. Here, we show that sorted IL-17+IFNγ- (pure Tc17 cells) cultured in vitro can convert to secreting IFNλ in the presence of IL-2 alone. Interestingly even in the presence of Tc17 skewing conditions, IL17-IFNγ+ (pure Tc1 cells) do not convert to IL-17 production. These data confirm our original observations showing the plasticity of the Tc17 phenotype - indeed, IL-2 may be sufficient to drive conversion in vitro. However, the molecular mechanisms behind CD8 T cell plasticity have yet to be elucidated; ongoing studies are examining the role of TCR affinity and various transcription factors in this process.
IL-15 differentially affects the migratory capacity of young and aged memory CD8 T cells to mucosal sites. (46.5)
Authors: Marzo Amanda , Sowell Ryan , Rogozinska Magdalena , Lerret Nadine 
Published: January 2023

Abstract
Given that CD4 T cells are targets of depletion by HIV and required for the homing capacity of CD8 T cells, enhancing recruitment of both CD4 and CD8’s could potentially enhance protection against HIV infection. CD8 T cells at the site of infection are critical for clearance of HIV-infected cells. Memory CD8 T cells migrate into the periphery in the absence of “CD4 help”, homeostatically. However, migration to mucosal tissues such as the gut, require up-regulation of chemokine receptors, intergrins and other signals to gain entry. γC cytokines are key components of CD4 and CD8 T cell survival and maintenance. To date, the specific role of γC cytokines on migration of antigen-specific memory CD8 T cells to mucosal tissues is poorly understood. We show that IL-15 complex treatment drives migration of memory CD8 T cells to mucosa tissues such as the lung and lamina propria of the small intestine (SI LP). However, if the memory cells are aged then migration of CD8 T cells to the mucosal tissues is limited to the lung. These data reveal a novel role of for IL-15 for use as a potential vaccine adjuvant to enhance migration of young memory CD8 T cells to mucosal sites of infection and enhance protection against HIV infection.
Cytokines establish T cell memory by regulating mitochondrial metabolism (46.7)
Authors: van der Windt Gerritje , Everts Bart , Curtis Jonathan , Freitas Tori , Amiel Eyal , Pearce Erika 
Published: January 2023

Abstract
CD8 T cells have a crucial role in host defense during infection. Upon activation, antigen-specific effector T cell populations will first expand and then contract, however, a portion of this population will persist as long-lived memory T cells that will mediate immunity to re-infection. Although this predictable pattern of CD8 T cell responses is well established, the underlying cellular mechanisms regulating the transition to memory T cells remain undefined. We speculate that during a primary response to infection, T cells experience metabolic stress, perhaps due to nutrient and/or growth factor limitation as the pathogen is cleared and antigen concentrations decline. Our previous work suggests that during this period, T cells need to switch from glycolysis to forms of catabolic metabolism, like fatty acid oxidation, in order to survive and develop into memory T cells. Using the Seahorse Extracellular Flux Analyzer, which measures cellular oxygen consumption and proton production, we are able to determine T cell metabolism in real-time. Currently we are investigating the alterations in T cell bioenergetics and mitochondrial function that are critical for the generation of memory T cells. Our recent data show that specific common γ chain cytokines regulate this process. These results offer new insight into the molecular mechanisms of how cytokines drive T cell fate during an immune response.
ST6Gal I promotes rapid IL-2Rα expression and early proliferation of terminal effector CD8 T cells (46.8)
Authors: Onami Thandi , Zeng Junwei , Patel Jenish , Rajini Bheemreddy , Kaech Susan , Smith Kendall 
Published: January 2023

Abstract
ST6Gal I is a glycosyltransferase highly expressed by lymphocytes and cancer cells that catalyzes the addition of α2,6 sialic acid to galactose (Siaα2-6Gal) on N-linked glycoproteins. We discovered that ST6Gal I shows dramatic changes in gene expression during memory CD8 T cell differentiation that corresponds with lectin binding, but the significance of this regulated carbohydrate modification remained a mystery. To identify the significance of these regulated glyco-phenotypic changes, we infected ST6Gal I-/- mice and found that viral-specific cell expansion was impaired. Moreover, defective viral-specific CD8 T cell expansion was due to early intrinsic defects in proliferation of terminal effector cells, whereas memory precursor development was enhanced. We provide direct evidence that loss of ST6Gal I expression by CD8 T cells resulted in delayed surface expression of IL-2Rα in vivo due to impaired IL-2/IL-2R signaling. These results suggest that CD8 T cells regulate ST6Gal I expression to promote proliferation induced by cytokine-dependent signaling.
A loss-of-function variant of the antiviral molecule MAVS is associated with a subset of systemic lupus patients (47.10)
Authors: Si-Tahar Mustapha , Niewold Timothy , Vitour Damien , Solhonne Brigitte , Crow Mary , Pothlichet Julien 
Published: January 2023

Abstract
Dysregulation of the antiviral immune response may contribute to autoimmune diseases. Here, we hypothesized that altered expression or function of MAVS, a key molecule downstream of the viral sensors RIG-I and MDA-5, may impair antiviral cell signaling and thereby influence the risk for systemic lupus erythematosus (SLE), the prototype autoimmune disease. We used molecular techniques to screen non-synonymous single-nucleotide polymorphisms (SNPs) in the MAVS gene for functional significance in human cell lines, and identified one critical loss-of-function variant (C79F, rs11905552). This SNP substantially reduced expression of type I interferon and other proinflammatory mediators, and was found almost exclusively in the African-American population. Importantly, in African-American SLE patients, the C79F allele was associated with low type I interferon production and absence of anti-RNA-binding protein antibodies. These serologic associations were not related to a distinct, functionally neutral, MAVS SNP Q198K. Hence, this is the first demonstration that an uncommon genetic variant in the MAVS gene has a functional impact upon the anti-viral interferon pathway in vivo in humans, and is associated with a novel sub-phenotype in SLE.
Protein phosphatase 2A facilitates IL-17 production by promoting accessibility to the IL-17 locus (47.15)
Authors: Apostolidis Sokratis , Crispin Jose , Rauen Thomas , Thai To-Ha , Tsokos George 
Published: January 2023

Abstract
Systemic lupus erythematosus (SLE) is a complex autoimmune disease caused by the combination of several immune abnormalities. T cells from SLE patients exhibit an aberrant phenotype, caused in part by increased levels of the protein phosphatase 2A (PP2A). To study the mechanisms through which PP2A alters T cell behavior and to identify the contribution of this defect to the disease, we generated a transgenic mouse that over-expresses PP2A in T cells. The transgenic mice produced abnormally high levels of IL-17A and F in vivo and in vitro. Remarkably, naïve CD4+ TPP2A cells produced IL-17 as early as 3h after stimulation. This effect was specific for IL-17 as production of type I and type II cytokines was not affected. PP2A over-expression did not promote Th17 differentiation or significant increases in Th17-related transcription factors. Due to the specificity of the phenomenon and its kinetics, we hypothesized that PP2A may facilitate transcription in the IL-17 locus. ChIP experiments revealed increased tri-methylation of H3K4 and decreased tri-methylation of H3K9 at the Il17a and Il17f promoters as well as in local conserved non-coding sequences. These changes are associated with increased chromatin accessibility. We propose that PP2A plays a central role in the transcriptional regulation of IL-17 by promoting chromatin accessibility to the IL-17 locus. This pathway may play a role in the excessive IL-17 production observed in SLE T cells.
HLA and T cell receptor associations in narcolepsy, a disorder associated with the selective loss of hypocretin neurons (47.17)
Authors: Mignot Emmanuel , Lin Ling , Faraco Juliette , Kornum Birgitte , Steinman Lawrence , Hallmayer Joachim 
Published: January 2023

Abstract
Narcolepsy is a life long disorder characterized by severe sleepiness and cataplexy. It affects 1 in 2,000 individuals and is caused by the selective loss of the hypocretin producing neurons in hypothalamus. This cell loss is likely to be autoimmune and recent findings are closing in on some of the key genetic and environmental effects involved. At the genetic level, the disorder is very tightly associated with DQA1*01:02/DQB1*06:02. In addition to the established role of HLA-DQ, a specific T Cell Receptor Alpha J segment polymorphism has been identified as another susceptibility factor. We are currently sequencing the T-cell TCR@ repertoire to explore this further in recent onset narcolepsy cases. At the level of environmental triggers, winter related upper airway infections are believed to be involved, e.g. we have reported an increased presence of antistreptolysin-O antibody, implicating a role for streptococcal infections. In China, studies of disease onset seasonality indicate a 16 fold increase in onset occurrence around spring when compared to early winter. We anticipate that the cause of narcolepsy will likely involve a specific antigen presentation by DQA1*01:02/DQB1*06:02 to a restricted number of pathogenic T-cell subtypes. As immune involvement is increasingly being recognized in neurodegenerative and neuropsychiatric disorders, understanding why the hypocretin neurons in narcolepsy die is likely to increase understanding of these other disorders as well.
CTLA4 1661 A/G polymorphisms in North Indian Celiac disease patients. (47.21)
Authors: Palhora Shilpa , Saikia Biman , Arora Sunil , Thapa B. , Lal Sadhna 
Published: January 2023

Abstract
Celiac disease or Gluten sensitive enteropathy is an immunomediated chronic small bowel disease caused by intolerance to prolamins,the proteic and alcohol soluble fractions of gluten,a major component of some of commonest cereal like wheat,rye and barley. Celiac Disease is an autoimmune disorder, characterised by villous atrophy of the small intestine, which results from a T-cell-mediated response to gluten-derived peptides. The cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) is involved in the regulation of T-cell activation and the CTLA4 1661 A/G polymorphism has been implicated in several autoimmune disorders, including celiac disease. The aim of this study is to determine the Genetic polymorphisms of the CTLA4 gene and genotyping of CTLA4-1661 A/G in celiac disease in the North Indian population. The 1661 A/G polymorphisms was genotyped in a case of 50 patients and 25 controls.The frequency of the 1661 G-allele was increased in celiac disease patients (p=0.013).The genotype distributions shows a significant difference between cases and controls.These results indicate the involvement of the CTLA4 gene in celiac disease development.The haplotype carrying the CTLA 4 1661 G allele was shown to be associated with disease. A larger patients and controls needs to be studied for further conclusive evidence. Statistical analysis was carried out using Microsoft Excel 2002 and SPSS 16 for Windows
Scleroderma signs in Tight Skin 2 mice develop progressively over time. (47.25)
Authors: Long Kristen , Artlett Carol , Blankenhorn Elizabeth 
Published: January 2023

Abstract
Systemic sclerosis (SSc) is an often fatal inflammatory autoimmune disease affecting connective tissue, characterized by excessive collagen deposition in skin and other organs. The Tight Skin (Tsk) 2 mouse model of disease has many features of human disease including tight skin, excessive collagen deposition, alterations in the extracellular matrix, and occurrence of antinuclear antibodies (ANA) with age. Since current treatments only ameliorate disease symptoms, the Tsk2/+ mouse is crucial for the understanding of disease pathology and progression, however, the Tsk2 gene has yet to be elucidated. Our lab has recently narrowed the interval containing the gene to 2.9 megabases. Understanding disease progression in this model is essential, and histological and total protein studies have shown that increased collagen accumulation does not occur until at least 10 weeks of age in Tsk2/+ mice, despite the “tight” phenotype occurring at 2 weeks. mRNA expression levels from the skin of young mice showed that Tsk2/+ mice have an up regulation of Col1a1, Col3a1, and Col5a2, as well as a robust expression of TGF-β signatures and extracellular matrix fibers. Histological studies revealed a significant increase of elastic bundles in the dermis of 2 week old Tsk2/+ mice. Aged Tsk2/+ mice produced ANA specific to severe disease after initial fibrosis, suggesting additional progression of the disease state. Our studies reveal a novel timeline of disease progression in the Tsk2/+ mouse.
Somatic KRAS mutations associated with a human non-malignant syndrome of autoimmunity and abnormal leukocyte homeostasis (47.4)
Authors: Lu Lianghao , Niemela Julie , Fleisher Thomas , Davis Joie , Caminha Iusta , Natter Mark , Beer Laurel , Dowdell Kennichi , Pittaluga Stefania , Raffeld Mark , Rao Koneti , Oliveira João Bosco 
Published: January 2023

Abstract
Autoimmune lymphoproliferative syndrome (ALPS) is a non-malignant disease characterized by early-onset chronic lymphadenopathy, splenomegaly, multilineage cytopenias, polyclonal hypergammaglobulinemia, expansion of circulating TCRαβ+B220+CD4-CD8- T (αβ+-DNT) lymphocytes, and an increased risk of B-cell lymphoma. Most ALPS patients have germline or somatic TNFRSF6 (FAS) mutations, and a small minority of patients have germline mutations in FAS ligand and caspase 10. We recently reported that an ALPS-like phenotype can be caused by a somatic NRAS mutation (G13D) resulting in the defective lymphocyte apoptosis. Here we demonstrate that somatic mutations in the related KRAS gene can also be associated with a non-malignant syndrome of autoimmunity and breakdown of leukocyte homeostasis. The activating KRAS mutation (G13C) impaired cytokine-withdrawal induced T cell apoptosis through the suppression of the pro-apoptotic protein BIM and facilitated proliferation through p27kip1 downregulation. These defects could be corrected by MEK1 or PI3K inhibition in vitro. We suggest the use of the term RAS-associated autoimmune leukoproliferative disease (RALD) to differentiate this disorder from ALPS. In the hematopoietic system, somatic KRAS and NRAS mutations are commonly observed in aggressive tumors such as multiple myeloma or juvenile myelomonocytic leukemia (JMML). From our reports, we think patients with somatic KRAS and NRAS mutations can follow a more benign clinical course.
Immunological synapses do not restrict secretion of interferon γ during antigen-specific lysis of target cells by CD-8+ cytotoxic T lymphocytes (48.12)
Authors: Sanderson Nicholas , Puntel Mariana , Kroeger Kurt , Bondale Niyati , Iranmanesh Niloufar , Swerdlow Mark , Ibrahim Ahmed , Castro Maria , Lowenstein Pedro 
Published: January 2023

Abstract
Cytotoxic T lymphocytes display two main effector mechanisms when interacting with target cells in an antigen-specific manner: (i) destruction of the target cell, and (ii) secretion of cytokines. It is thought that while target cell lysis occurs following brief contact with the T cell, cytokine secretion requires formation of immunological synapses between T cells and target cells. At immunological synapses between CTLs and adenovirus-infected astrocytes in the brain, interferon γ is polarized at the contact, suggesting immunological synapses constrain secretion of interferon γ. To test this hypothesis we developed a live cell imaging system to examine whether individual OT-I T cells interacting with individual ovalbumin-expressing astrocytes (cultured on a monolayer of ovalbumin non-expressing astrocytes) secrete interferon γ in a vectorial or diffuse manner. In this paradigm, OT-I T cells form contacts with targets lasting for several hours, during which interferon γ secretion is always observed, and approximately 50% of targets are lysed. Interferon γ secretion appears to be diffuse, acting equally on targets and non-antigenic neighbors. Our data indicate that secretion of interferon γ is not restricted spatially by immunological synapses.
Tyrosinase reactive T cells can eliminate large established human melanoma tumors in vivo (48.23)
Authors: Martins da Palma Telma , Spivey Natali , Naga Osama , Al-Khami Amir , Graves Michael , Lesher Aaron , Ferrone Soldano , Mehrotra Shikhar , Norell Håkan , Nishimura Michael 
Published: January 2023

Abstract
Objective clinical responses of melanoma can be achieved by infusion of tumor infiltrating lymphocytes or T cell receptor (TCR) gene transduced T cells. To evaluate the therapeutic efficacy of T cells expressing a high affinity TCR specific for the tyrosinase melanoma antigen (epitope Tyr368-376), we have developed a xenogenic model of human melanoma. Established human melanoma tumors (624 MEL) were rejected by administering low numbers of TIL 1383I TCR transgenic (h3T) splenocytes in an antigen specific, HLA-A2 restricted manner. Importantly, this therapeutic effect was observed with both small (30mm3) and large (100mm3) tumors. However, many of the mice that rejected their tumors recurred in time and the recurrent tumor cells were no longer recognized by h3T cells in vitro or in vivo. Phenotypic analysis revealed that all recurrent tumors from mice bearing 624 MEL had specifically lost HLA-A2, but not other MHC class I alleles, and this was not restored by IFN-γ treatment. Interestingly, mice bearing a HLA-A2 positive clone of 624 MEL (624-38 MEL) did not exhibit any tumor recurrences when treated with h3T cells. These results highlight the limitations of using a monoclonal therapeutic approach for melanoma. They also stress the need of models that enable us to evaluate combinatory therapies targeting heterogeneous tumors to develop improved immunotherapeutic strategies.
Enhancing NK cell-mediated tumor rejection by activation of the aryl hydrocarbon receptor (48.31)
Authors: Sunwoo John , Shin June , Zhang Luhua , Murillo Oihana , Kim Junmo 
Published: January 2023

Abstract
Natural killer (NK) cells’ tumoricidal effector activity is regulated by a balance of inhibitory and activating receptors. We demonstrate that murine NK cells express a cytoplasmic receptor called the aryl hydrocarbon receptor (AhR). AhR is upregulated upon NK cell activation and binds a wide range of endogenous and exogenous ligands. Upon binding agonistic ligands, this receptor translocates to the nucleus and regulates transcription. We show that activation of AhR in NK cells enhances IFNγ production by stimulated NK cells. Furthermore, activation of AhR in vivo results in enhanced rejection of RMA-S tumors in an NK cell - dependent and AhR - dependent manner. This rejection is correlated with an increase in tumor-infiltrating NK cells. Importantly, this rejection of RMA-S tumors is not the result of the AhR agonist’s effects on the tumor cells directly because RMA-S cells do not express AhR, and their proliferation rate in vivo is not affected by exposure to the ligands. This function of AhR as a potential enhancer of NK cell activity is likely to be physiologic because we also find that AhR-deficient mice are not able to control RMA-S tumors. We show that this defect is inherent to the NK cells themselves using an adoptive transfer approach. Thus, we conclude that AhR plays an important role in the modulation of NK cell effector functions and that activation of this receptor may be a novel therapeutic strategy for cancer treatment and prevention.
Systemic inhibition of IKKβ for the treatment of malignant melanoma profoundly alters the leukocytic composition within the tumor and lymphoid organs (48.32)
Authors: Hawkins Oriana , Horton Linda , Ayers Gregory , Richmond Ann 
Published: January 2023

Abstract
With over 8500 deaths each year in the USA, malignant melanoma is the deadliest of all skin cancers. Constitutive activation of the nuclear factor kappa B (NF-κB) is common in melanoma, promoting tumor growth, survival and metastasis. In light of its role in tumorigenesis, targeting of the NF-κB pathway is a therapeutic option for the treatment of melanoma. However, NF- κB activation is critical for the development, survival, migration and function of immune cells. We hypothesized that systemic inhibition of NF- κB activation might have a deleterious effect on the tumor immune response. Melanoma bearing C57BL/6 mice received 100 mg/kg of BMS-345541, a selective inhibitor of the inhibitor of κB kinase (IKKβ), twice daily. Tumors, spleens and bone marrow were harvested at different time points and analyzed by flow cytometry for leukocyte composition. There was a profound reduction of B cells and immature myeloid cells in the spleen and bone marrow, as well as an overall reduction in leukocytic infiltration of the tumor. Unexpected was the increase in the proportion of CD8+ T cells at all sites. These data suggest a shift from a pro-inflammatory and pro-tumorigenic leukocytic profile to an anti-tumor profile. The implications of these findings are explored.
Morphine inhibits recruitment of tumor promoting leukocytes (48.33)
Authors: Koodie Lisa , Ramakrishnan Sundaram , Yu Haidong , Charboneau Richard , Liu Xiuiu , Roy Sabita 
Published: January 2023

Abstract
Tumor cells initiate angiogenesis within the tumor micro-environment. The maintenance of these newly formed vessels is highly dependent on the migration and recruitment of immune cells. In previous studies, we have demonstrated that chronic morphine administration suppresses tumor cell induced angiogenesis to inhibit tumor growth in mice. Here we tested the hypothesis that a known immunosuppressant as morphine also regulates immune cell recruitment into- and migration towards a tumor microenvironment. To mimic a tumor microenvironment, matrigel was admixed with conditioned media derived from Lewis lung carcinoma cells (LLCCM) and implanted subcutaneous in WT or Mu-Opioid Receptor knockout mice (MORKO) treated with saline or morphine through pellet implantation. Interestingly, plugs taken from placebo treated mice (day 7) showed significant leukocyte infiltration, greater than that compared to plugs from morphine treated mice (p&lt;0.05) and this effect was abolished in MORKO mice. Similarly, morphine suppressed the recruitment of adoptively transferred luciferase expressing bone marrow derived cells (known to contribute to tumor growth) into PVA sponges-presoaked with LLCCM and implanted subcutaneous in mice- pretreated with placebo or morphine. Taken together, these studies suggest that morphine treatment can potentially decrease solid tumor associated inflammation to reduce angiogenesis associated with increased tumor growth.