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Item The Complexity of Microglial Interactions With Innate and Adaptive Immune Cells in Alzheimer’s Disease(Frontiers Media, 2020-11-19) Wyatt-Johnson, Season K.; Brutkiewicz, Randy R.; Microbiology and Immunology, School of MedicineIn the naïve mouse brain, microglia and astrocytes are the most abundant immune cells; however, there is a complexity of other immune cells present including monocytes, neutrophils, and lymphocytic cells, such as natural killer (NK) cells, T cells, and B cells. In Alzheimer’s disease (AD), there is high inflammation, reactive microglia, and astrocytes, leaky blood–brain barrier, the buildup of amyloid-beta (Aβ) plaques, and neurofibrillary tangles which attract infiltrating peripheral immune cells that are interacting with the resident microglia. Limited studies have analyzed how these infiltrating immune cells contribute to the neuropathology of AD and even fewer have analyzed their interactions with the resident microglia. Understanding the complexity and dynamics of how these immune cells interact in AD will be important for identifying new and novel therapeutic targets. Thus, this review will focus on discussing our current understanding of how macrophages, neutrophils, NK cells, T cells, and B cells, alongside astrocytes, are altered in AD and what this means for the disorder, as well as how these cells are affected relative to the resident microglia.Item Dichotomous effects of cellular expression of STAT3 on tumor growth of HNSCC(Elsevier, 2021) Bickett, Thomas E.; Knitz, Michael W.; Piper, Miles; Oweida, Ayman J.; Gadwa, Jacob; Darragh, Laurel B.; Nguyen, Diemmy; Bhatia, Shilpa; Bhuvane, Shiv; Phan, Andy V.; Van Court, Benjamin; Corbo, Sophia; Pham, Tiffany; Dent, Alexander L.; Lenz, Laurel; Karam, Sana D.; Microbiology and Immunology, School of MedicineSTAT3 signaling has been shown to regulate cellular function and cytokine production in the tumor microenvironment (TME). Within the head and neck squamous cell carcinoma (HNSCC) TME, we previously showed that therapeutic targeting of STAT3 in combination with radiation resulted in improved tumor growth delay. However, given the independent regulatory effects STAT3 has on anti-tumor immunity, we aimed to decipher the effects of individually targeting STAT3 in the cancer cell, regulatory T cells (Tregs), and natural killer (NK) cell compartments in driving tumor growth and resistance to therapy in HNSCCs. We utilized a CRISPR knockout system for genetic deletion of STAT3 within the cancer cell as well as two genetic knockout mouse models, FoxP3-Cre/STAT3 fl and NKp46-Cre/STAT3 fl, for Tregs and NK cell targeting, respectively. Our data revealed differences in development of resistance to treatment with STAT3 CRISPR knockout in the cancer cell, driven by differential recruitment of immune cells. Knockout of STAT3 in Tregs overcomes this resistance and results in Treg reprogramming and recruitment and activation of antigen-presenting cells. In contrast, knockout of STAT3 in the NK cell compartment results in NK cell inactivation and acceleration of tumor growth. These data underscore the complex interplay between the cancer cell and the immune TME and carry significant implications for drug targeting and design of combination approaches in HNSCCs.Item Effects of Soy Peptide on Dendritic Cells(Office of the Vice Chancellor for Research, 2013-04-05) Shipman, Kaylee; Tung, Chun-Yu; Han, Ling; Patel, Amy; Corn, Caleb; Chang, Hua-ChenInnate immunity is mediated by effector cells, including NK cells, dendritic cells (DCs), macrophages, and polymorphonuclear phagocytes, which can respond immediately after activation through receptors encoded by germ-line genes. Innate immune responses represent the first line of defense in immunosurveillance. Interventions that enhance the functions of innate immunity will be an important armamentarium to human health. We recently exploited a natural dietary soy peptide called lunasin to improve the immune functions. The hypothesis was that lunasin peptide has stimulatory effects on immune cells. To test this hypothesis, human peripheral blood mononuclear cells (PBMCs) of healthy donors were stimulated with or without lunasin. We found that lunasin is capable of stimulating DCs to up-regulate chemokines (CCL2, CCL3, and CCL4), cytokines (TNFα and IFNα), and co-stimulatory molecules (CD80, CD86). In addition, lunasin-treated DCs can provide NK with required signals for activation. Taken together, our results support the immunomodulatory activity of soy peptide on DCs, which leads to enhancement of innate immunity.Item Functional expression of CD73 on human natural killer cells(Springer, 2022) Chambers, Andrea M.; Wang, Jiao; Dao, Tram N.; Lupo, Kyle B.; Veenhuis, Paige; Ayers, Mitchell G.; Slivova, Veronika; Cohen‑Gadol, Aaron A.; Matosevic, Sandro; Neurological Surgery, School of MedicineThe production of adenosine by CD73 on cancer cells in the tumor microenvironment is a recognized immunosuppressive mechanism contributing to immune evasion in many solid tumors. While NK cells have been purported to overexpress CD73 under certain conditions, this phenomenon has remained elusive and unclear. We have found that while NK cells are able to upregulate expression of CD73 on their surface when exposed to CD73+ cancer cells, this upregulation is not universal, nor is it often substantial. Rather, our data point to the extent of CD73 expression on NK cells to be both cancer-specific and environmentally-driven, and largely limited in intensity. We found that NK cell overexpression of CD73 responds to the level of CD73 on cancer cells and is enhanced in hypoxia. Interestingly, human CD73+ NK cells appear hyperfunctional in vitro compared to CD73- NK cells, suggesting that CD73 expression could be a bystander of NK cell activation. In addition, glioblastoma patient data show that tumor-infiltrating NK cells express CD73 variably, depending on donor, and present lower expression of CD16, alongside patient-specific changes in CEACAM1, CXCR3 and TIM-3, suggesting some functional changes in NK cell responses associated with expression of CD73 on NK cells in vivo. Taken together, our study is the first to show that while NK cells are largely resistant to the upregulation of CD73, CD73 expression is inducible on NK cells in response to CD73 on cancer cells, and these cells are associated with distinct functional signatures.Item Functional expression of CD73 on human natural killer cells(Springer, 2022-12) Chambers, Andrea M.; Wang, Jiao; Dao, Tram N.; Lupo, Kyle B.; Veenhuis, Paige; Ayers, Mitchell G.; Slivova, Veronika; Cohen-Gadol, Aaron A.; Matosevic, Sandro; Neurological Surgery, School of MedicineThe production of adenosine by CD73 on cancer cells in the tumor microenvironment is a recognized immunosuppressive mechanism contributing to immune evasion in many solid tumors. While NK cells have been purported to overexpress CD73 under certain conditions, this phenomenon has remained elusive and unclear. We have found that while NK cells are able to upregulate expression of CD73 on their surface when exposed to CD73+ cancer cells, this upregulation is not universal, nor is it often substantial. Rather, our data point to the extent of CD73 expression on NK cells to be both cancer-specific and environmentally-driven, and largely limited in intensity. We found that NK cell overexpression of CD73 responds to the level of CD73 on cancer cells and is enhanced in hypoxia. Interestingly, human CD73+ NK cells appear hyperfunctional in vitro compared to CD73− NK cells, suggesting that CD73 expression could be a bystander of NK cell activation. In addition, glioblastoma patient data show that tumor-infiltrating NK cells express CD73 variably, depending on donor, and present lower expression of CD16, alongside patient-specific changes in CEACAM1, CXCR3 and TIM-3, suggesting some functional changes in NK cell responses associated with expression of CD73 on NK cells in vivo. Taken together, our study is the first to show that while NK cells are largely resistant to the upregulation of CD73, CD73 expression is inducible on NK cells in response to CD73 on cancer cells, and these cells are associated with distinct functional signatures.Item Functional expression of CD73 on human natural killer cells(Springer, 2022) Chambers, Andrea M.; Wang, Jiao; Dao, Tram N.; Lupo, Kyle B.; Veenhuis, Paige; Ayers, Mitchell G.; Slivova, Veronika; Cohen‑Gadol, Aaron A.; Matosevic, Sandro; Neurological Surgery, School of MedicineThe production of adenosine by CD73 on cancer cells in the tumor microenvironment is a recognized immunosuppressive mechanism contributing to immune evasion in many solid tumors. While NK cells have been purported to overexpress CD73 under certain conditions, this phenomenon has remained elusive and unclear. We have found that while NK cells are able to upregulate expression of CD73 on their surface when exposed to CD73+ cancer cells, this upregulation is not universal, nor is it often substantial. Rather, our data point to the extent of CD73 expression on NK cells to be both cancer-specific and environmentally-driven, and largely limited in intensity. We found that NK cell overexpression of CD73 responds to the level of CD73 on cancer cells and is enhanced in hypoxia. Interestingly, human CD73+ NK cells appear hyperfunctional in vitro compared to CD73− NK cells, suggesting that CD73 expression could be a bystander of NK cell activation. In addition, glioblastoma patient data show that tumor-infiltrating NK cells express CD73 variably, depending on donor, and present lower expression of CD16, alongside patient-specific changes in CEACAM1, CXCR3 and TIM-3, suggesting some functional changes in NK cell responses associated with expression of CD73 on NK cells in vivo. Taken together, our study is the first to show that while NK cells are largely resistant to the upregulation of CD73, CD73 expression is inducible on NK cells in response to CD73 on cancer cells, and these cells are associated with distinct functional signatures.Item Mirc11 Disrupts Inflammatory but Not Cytotoxic Responses of NK Cells(AACR, 2019-10) Nanbakhsh, Arash; Srinivasamani, Anupallavi; Holzhauer, Sandra; Riese, Matthew J.; Zheng, Yongwei; Wang, Demin; Burns, Robert; Reimer, Michael H.; Rao, Sridhar; Lemke, Angela; Tsaih, Shirng-Wern; Flister, Michael J.; Lao, Shunhua; Dahl, Richard; Thakar, Monica S.; Malarkannan, Subramaniam; Microbiology and Immunology, School of MedicineNatural killer (NK) cells generate proinflammatory cytokines that are required to contain infections and tumor growth. However, the posttranscriptional mechanisms that regulate NK cell functions are not fully understood. Here, we define the role of the microRNA cluster known as Mirc11 (which includes miRNA-23a, miRNA-24a, and miRNA-27a) in NK cell–mediated proinflammatory responses. Absence of Mirc11 did not alter the development or the antitumor cytotoxicity of NK cells. However, loss of Mirc11 reduced generation of proinflammatory factors in vitro and interferon-γ–dependent clearance of Listeria monocytogenes or B16F10 melanoma in vivo by NK cells. These functional changes resulted from Mirc11 silencing ubiquitin modifiers A20, Cbl-b, and Itch, allowing TRAF6-dependent activation of NF-κB and AP-1. Lack of Mirc11 caused increased translation of A20, Cbl-b, and Itch proteins, resulting in deubiquitylation of scaffolding K63 and addition of degradative K48 moieties on TRAF6. Collectively, our results describe a function of Mirc11 that regulates generation of proinflammatory cytokines from effector lymphocytes.Item Strategies to induce natural killer cell tolerance in xenotransplantation(Frontiers Media, 2022-08-22) Lopez, Kevin J.; Cross-Najafi, Arthur A.; Farag, Kristine; Obando, Benjamin; Thadasina, Deepthi; Isidan, Abdulkadir; Park, Yujin; Zhang, Wenjun; Ekser, Burcin; Li, Ping; Surgery, School of MedicineEliminating major xenoantigens in pig cells has drastically reduced human antibody-mediated hyperacute xenograft rejection (HXR). Despite these advancements, acute xenograft rejection (AXR) remains one of the major obstacles to clinical xenotransplantation, mediated by innate immune cells, including macrophages, neutrophils, and natural killer (NK) cells. NK cells play an ‘effector’ role by releasing cytotoxicity granules against xenogeneic cells and an ‘affecter’ role on other immune cells through cytokine secretion. We highlight the key receptor-ligand interactions that determine the NK cell response to target cells, focusing on the regulation of NK cell activating receptor (NKG2D, DNAM1) and inhibitory receptor (KIR2DL1-4, NKG2A, and LIR-1) signaling pathways. Inhibition of NK cell activity may protect xenografts from cytotoxicity. Recent successful approaches to reducing NK cell-mediated HXR and AXR are reviewed, including genetic modifications of porcine xenografts aimed at improving pig-to-human compatibility. Future directions to promote xenograft acceptance are discussed, including NK cell tolerance in pregnancy and NK cell evasion in viral infection.