Browsing by Subject "CD8-Positive T-Lymphocytes"

Now showing 1 - 8 of 8
  • Thumbnail Image
    Item
    Alefacept provides sustained clinical and immunological effects in new-onset type 1 diabetes patients
    (American Society for Clinical Investigation, 2015-08-03) Rigby, Mark R.; Harris, Kristina M.; Pinckney, Ashley; DiMeglio, Linda A.; Rendell, Marc S.; Felner, Eric I.; Dostou, Jean M.; Gitelman, Stephen E.; Griffin, Kurt J.; Tsalikian, Eva; Gottlieb, Peter A.; Greenbaum, Carla J.; Sherry, Nicole A.; Moore, Wayne V.; Monzavi, Roshanak; Willi, Steven M.; Raskin, Philip; Keyes-Elstein, Lynette; Long, S. Alice; Kanaparthi, Sai; Lim, Noha; Phippard, Deborah; Soppe, Carol L.; Fitzgibbon, Margret L.; McNamara, James; Nepom, Gerald T.; Ehlers, Mario R.; Department of Pediatrics, IU School of Medicine
    BACKGROUND: Type 1 diabetes (T1D) results from destruction of pancreatic β cells by autoreactive effector T cells. We hypothesized that the immunomodulatory drug alefacept would result in targeted quantitative and qualitative changes in effector T cells and prolonged preservation of endogenous insulin secretion by the remaining β cells in patients with newly diagnosed T1D. METHODS: In a multicenter, randomized, double-blind, placebo-controlled trial, we compared alefacept (two 12-week courses of 15 mg/wk i.m., separated by a 12-week pause) with placebo in patients with recent onset of T1D. Endpoints were assessed at 24 months and included meal-stimulated C-peptide AUC, insulin use, hypoglycemic events, and immunologic responses. RESULTS: A total of 49 patients were enrolled. At 24 months, or 15 months after the last dose of alefacept, both the 4-hour and the 2-hour C-peptide AUCs were significantly greater in the treatment group than in the control group (P = 0.002 and 0.015, respectively). Exogenous insulin requirements were lower (P = 0.002) and rates of major hypoglycemic events were about 50% reduced (P < 0.001) in the alefacept group compared with placebo at 24 months. There was no apparent between-group difference in glycemic control or adverse events. Alefacept treatment depleted CD4+ and CD8+ central memory T cells (Tcm) and effector memory T cells (Tem) (P < 0.01), preserved Tregs, increased the ratios of Treg to Tem and Tcm (P < 0.01), and increased the percentage of PD-1+CD4+ Tem and Tcm (P < 0.01). CONCLUSIONS: In patients with newly diagnosed T1D, two 12-week courses of alefacept preserved C-peptide secretion, reduced insulin use and hypoglycemic events, and induced favorable immunologic profiles at 24 months, well over 1 year after cessation of therapy. TRIAL REGISTRATION: https://clinicaltrials.gov/ NCT00965458. FUNDING: NIH and Astellas.
  • Thumbnail Image
    Item
    Autophagy modulates CD4+ T-cell lineage recommitment upon pathogen infection
    (Springer Nature, 2020-07) Yang, Kai; Chi, Hongbo; Pediatrics, School of Medicine
  • Thumbnail Image
    Item
    Cutting Edge: Elevated Glycolytic Metabolism Limits the Formation of Memory CD8+ T Cells in Early Life
    (American Association of Immunologists, 2019-11-15) Tabilas, Cybelle; Wang, Jocelyn; Liu, Xiaojing; Locasale, Jason W.; Smith, Norah L.; Rudd, Brian D.; Pediatrics, School of Medicine
    Neonates often develop poor immunity against intracellular pathogens. Because CD8+ T cells are essential for eliminating infectious agents, it is crucial to understand why they behave differently in early life. Previous studies in mice have demonstrated that neonatal CD8+ T cells fail to form memory because of an intrinsic propensity to differentiate into short-lived effectors. However, the underlying mechanisms remain undefined. We now show that neonatal CD8+ T cells exhibit higher glycolytic activity than adult CD8+ T cells postinfection, which may be due to age-related differences in Lin28b expression. Importantly, when glycolysis is pharmacologically inhibited, the impaired formation of neonatal memory CD8+ T cells can be restored. Collectively, these data suggest that neonatal CD8+ T cells are inherently biased toward undergoing glycolytic metabolism postinfection, which compromises their ability to develop into memory CD8+ T cells in early life.
  • Thumbnail Image
    Item
    Mechanisms of innate and adaptive immunity to the Pfizer-BioNTech BNT162b2 vaccine
    (Springer Nature, 2022) Li, Chunfeng; Lee, Audrey; Grigoryan, Lilit; Arunachalam, Prabhu S.; Scott, Madeleine K.D.; Trisal, Meera; Wimmers, Florian; Sanyal, Mrinmoy; Weidenbacher, Payton A.; Feng, Yupeng; Adamska, Julia Z.; Valore, Erika; Wang, Yanli; Verma, Rohit; Reis, Noah; Dunham, Diane; O’Hara, Ruth; Park, Helen; Luo, Wei; Gitlin, Alexander D.; Kim, Peter; Khatri, Purvesh; Nadeau, Kari C.; Pulendran, Bali; Microbiology and Immunology, School of Medicine
    Despite the success of the BNT162b2 mRNA vaccine, the immunological mechanisms that underlie its efficacy are poorly understood. Here we analyzed the innate and adaptive responses to BNT162b2 in mice, and show that immunization stimulated potent antibody and antigen-specific T cell responses, as well as strikingly enhanced innate responses after secondary immunization, which was concurrent with enhanced serum interferon (IFN)-γ levels 1 d following secondary immunization. Notably, we found that natural killer cells and CD8+ T cells in the draining lymph nodes are the major producers of this circulating IFN-γ. Analysis of knockout mice revealed that induction of antibody and T cell responses to BNT162b2 was not dependent on signaling via Toll-like receptors 2, 3, 4, 5 and 7 nor inflammasome activation, nor the necroptosis or pyroptosis cell death pathways. Rather, the CD8+ T cell response induced by BNT162b2 was dependent on type I interferon-dependent MDA5 signaling. These results provide insights into the molecular mechanisms by which the BNT162b2 vaccine stimulates immune responses.
  • Thumbnail Image
    Item
  • Thumbnail Image
    Item
    STAT3 in tumor fibroblasts promotes an immunosuppressive microenvironment in pancreatic cancer
    (Cold Spring Harbor Laboratory, 2022-07-08) Lefler, Julia E.; MarElia-Bennett, Catherine B.; Thies, Katie A.; Hildreth, Blake E., III.; Sharma, Sudarshana M.; Pitarresi, Jason R.; Han, Lu; Everett, Caroline; Koivisto, Christopher; Cuitino, Maria C.; Timmers, Cynthia D.; O'Quinn, Elizabeth; Parrish, Melodie; Romeo, Martin J.; Linke, Amanda J.; Hobbs, G. Aaron; Leone, Gustavo; Guttridge, Denis C.; Zimmers, Teresa A.; Lesinski, Gregory B.; Ostrowski, Michael C.; Anatomy, Cell Biology and Physiology, School of Medicine
    Pancreatic ductal adenocarcinoma (PDAC) is associated with an incredibly dense stroma, which contributes to its recalcitrance to therapy. Cancer-associated fibroblasts (CAFs) are one of the most abundant cell types within the PDAC stroma and have context-dependent regulation of tumor progression in the tumor microenvironment (TME). Therefore, understanding tumor-promoting pathways in CAFs is essential for developing better stromal targeting therapies. Here, we show that disruption of the STAT3 signaling axis via genetic ablation of Stat3 in stromal fibroblasts in a Kras G12D PDAC mouse model not only slows tumor progression and increases survival, but re-shapes the characteristic immune-suppressive TME by decreasing M2 macrophages (F480+CD206+) and increasing CD8+ T cells. Mechanistically, we show that loss of the tumor suppressor PTEN in pancreatic CAFs leads to an increase in STAT3 phosphorylation. In addition, increased STAT3 phosphorylation in pancreatic CAFs promotes secretion of CXCL1. Inhibition of CXCL1 signaling inhibits M2 polarization in vitro. The results provide a potential mechanism by which CAFs promote an immune-suppressive TME and promote tumor progression in a spontaneous model of PDAC.
  • Thumbnail Image
    Item
    Targeting the chromatin effector Pygo2 promotes cytotoxic T cell responses and overcomes immunotherapy resistance in prostate cancer
    (American Association for the Advancement of Science, 2023) Zhu, Yini; Zhao, Yun; Wen, Jiling; Liu, Sheng; Huang, Tianhe; Hatial, Ishita; Peng, Xiaoxia; Al Janabi, Hawraa; Huang, Gang; Mittlesteadt, Jackson; Cheng, Michael; Bhardwaj, Atul; Ashfeld, Brandon L.; Kao, Kenneth R.; Maeda, Dean Y.; Dai, Xing; Wiest, Olaf; Blagg, Brian S. J.; Lu, Xuemin; Cheng, Liang; Wan, Jun; Lu, Xin; Medical and Molecular Genetics, School of Medicine
    The noninflamed microenvironment in prostate cancer represents a barrier to immunotherapy. Genetic alterations underlying cancer cell-intrinsic oncogenic signaling are increasingly appreciated for their role in shaping the immune landscape. Recently, we identified Pygopus 2 (PYGO2) as the driver oncogene for the amplicon at 1q21.3 in prostate cancer. Here, using transgenic mouse models of metastatic prostate adenocarcinoma, we found that Pygo2 deletion decelerated tumor progression, diminished metastases, and extended survival. Pygo2 loss augmented the activation and infiltration of cytotoxic T lymphocytes (CTLs) and sensitized tumor cells to T cell killing. Mechanistically, Pygo2 orchestrated a p53/Sp1/Kit/Ido1 signaling network to foster a microenvironment hostile to CTLs. Genetic or pharmacological inhibition of Pygo2 enhanced the antitumor efficacy of immunotherapies using immune checkpoint blockade (ICB), adoptive cell transfer, or agents inhibiting myeloid-derived suppressor cells. In human prostate cancer samples, Pygo2 expression was inversely correlated with the infiltration of CD8+ T cells. Analysis of the ICB clinical data showed association between high PYGO2 level and worse outcome. Together, our results highlight a potential path to improve immunotherapy using Pygo2-targeted therapy for advanced prostate cancer.
  • Thumbnail Image
    Item
    The Transcription Factor Bhlhe40 Programs Mitochondrial Regulation of Resident CD8+ T Cell Fitness and Functionality
    (Elsevier, 2019-09-17) Li, Chaofan; Zhu, Bibo; Son, Young Min; Wang, Zheng; Jiang, Li; Xiang, Min; Ye, Zhenqing; Beckermann, Kathryn E.; Wu, Yue; Jenkins, James W.; Siska, Peter J.; Vincent, Benjamin G.; Prakash, Y. S.; Peikert, Tobias; Edelson, Brian T.; Taneja, Reshma; Kaplan, Mark H.; Rathmell, Jeffrey C.; Dong, Haidong; Hitosugi, Taro; Sun, Jie; Microbiology and Immunology, School of Medicine