Browsing by Subject "T cell"
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Item CD4+ T cell expression of the IL-10 receptor is necessary for facial motoneuron survival after axotomy(BMC, 2020) Runge, Elizabeth M.; Iyer, Abhirami K.; Setter, Deborah O.; Kennedy, Felicia M.; Sanders, Virginia M.; Jones, Kathryn J.; Anatomy and Cell Biology, School of MedicineBackground: After peripheral nerve transection, facial motoneuron (FMN) survival depends on an intact CD4+ T cell population and a central source of interleukin-10 (IL-10). However, it has not been determined previously whether CD4+ T cells participate in the central neuroprotective IL-10 cascade after facial nerve axotomy (FNA). Methods: Immunohistochemical labeling of CD4+ T cells, pontine vasculature, and central microglia was used to determine whether CD4+ T cells cross the blood-brain barrier and enter the facial motor nucleus (FMNuc) after FNA. The importance of IL-10 signaling in CD4+ T cells was assessed by performing adoptive transfer of IL-10 receptor beta (IL-10RB)-deficient CD4+ T cells into immunodeficient mice prior to injury. Histology and qPCR were utilized to determine the impact of IL-10RB-deficient T cells on FMN survival and central gene expression after FNA. Flow cytometry was used to determine whether IL-10 signaling in T cells was necessary for their differentiation into neuroprotective subsets. Results: CD4+ T cells were capable of crossing the blood-brain barrier and associating with reactive microglial nodules in the axotomized FMNuc. Full induction of central IL-10R gene expression after FNA was dependent on CD4+ T cells, regardless of their own IL-10R signaling capability. Surprisingly, CD4+ T cells lacking IL-10RB were incapable of mediating neuroprotection after axotomy and promoted increased central expression of genes associated with microglial activation, antigen presentation, T cell co-stimulation, and complement deposition. There was reduced differentiation of IL-10RB-deficient CD4+ T cells into regulatory CD4+ T cells in vitro. Conclusions: These findings support the interdependence of IL-10- and CD4+ T cell-mediated mechanisms of neuroprotection after axotomy. CD4+ T cells may potentiate central responsiveness to IL-10, while IL-10 signaling within CD4+ T cells is necessary for their ability to rescue axotomized motoneuron survival. We propose that loss of IL-10 signaling in CD4+ T cells promotes non-neuroprotective autoimmunity after FNA.Item Endoplasmic Reticulum Calcium in the Pathogenesis of Type 1 Diabetes(2023-12) Weaver, Staci Anne; Evans-Molina, Carmella; Roh, Hyun Cheol; Sims, Emily K.; Wek, Ronald C.Type 1 diabetes (T1D) accounts for 5-10% of all diabetes cases and results from immune-mediated destruction of pancreatic β-cells. Individuals with Darier Disease, which is caused by loss of function germline mutation(s) in the sarcoendoplasmic reticulum Ca2+-ATPase pump (SERCA2) gene, have an elevated risk of being diagnosed with T1D (risk ratio, 1.74; 95% CI, 1.13-2.69), suggesting a potential mechanistic relationship between SERCA2 and T1D pathogenesis. To determine the impact of reduced SERCA2 expression on T1D pathogenesis, we generated SERCA2 haploinsufficient mice by backcrossing C57BL6/J-S2+/- mice onto the non-obese diabetic (NOD) background (NOD-S2+/- mice). Female NOD-S2+/- mice showed accelerated T1D onset (14wks vs. 18wks, p<0.0001), elevated circulating anti-insulin antibodies, and increased immune cell infiltration into the islets compared to NOD-WT mice. Single-cell RNA sequencing (scRNA-seq) on islets and spatial proteomics on pancreatic lymph node (PLN) and spleen at 6 wks of age revealed increased immune cell presence in islets and enhanced B and T cell activation in PLN and spleen of NOD-S2+/- mice. Furthermore, scRNA-seq on isolated islets revealed temporal alterations in pathways related to mitochondria function in β cells, and mechanistic studies revealed decreased glucose-stimulated ATP production, reduced mitochondrial membrane potential, decreased islet expression of ATP synthase/mitochondrial complex III, increased mitochondrial Ca2+, and altered mitochondrial ultrastructure in NOD-S2+/- islets at 10 wks of age. In co-culture experiments, NOD-S2+/- B cells showed increased activation and NOD-S2+/- T cells showed increased proliferation and activation when cultured with NOD-WT islets. Interestingly, NOD-S2+/- islets induced B and T cell proliferation and T cell activation when cultured with NOD-WT immune cells. Lastly, administration of a small molecule SERCA activator in NOD-S2+/- mice decreased immune cell infiltration into the islet and delayed T1D onset. In summary, our results demonstrate a novel pathway whereby modulation of SERCA2 impacts islet mitochondrial function, islet immunogenicity, and immune cell proliferation and activation which fuel progression to T1D.Item Enteropathy-associated T cell lymphoma subtypes are characterized by loss of function of SETD2(Rockefeller University Press, 2017-05-01) Moffitt, Andrea B.; Ondrejka, Sarah L.; McKinney, Matthew; Rempel, Rachel E.; Goodlad, John R.; Teh, Chun Huat; Leppa, Sirpa; Mannisto, Susanna; Kovanen, Panu E.; Tse, Eric; Au-Yeung, Rex K.H.; Kwong, Yok-Lam; Srivastava, Gopesh; Iqbal, Javeed; Yu, Jiayu; Naresh, Kikkeri; Villa, Diego; Gascoyne, Randy D.; Said, Jonathan; Czader, Magdalena B.; Chadburn, Amy; Richards, Kristy L.; Rajagopalan, Deepthi; Davis, Nicholas S.; Smith, Eileen C.; Palus, Brooke C.; Tzeng, Tiffany J.; Healy, Jane A.; Lugar, Patricia L.; Datta, Jyotishka; Love, Cassandra; Levy, Shawn; Dunson, David B.; Zhuang, Yuan; Hsi, Eric D.; Dave, Sandeep S.; Pathology and Laboratory Medicine, School of MedicineEnteropathy-associated T cell lymphoma (EATL) is the most common oncologic complication of celiac disease. Moffitt and colleagues identify novel EATL-defining mutations in SETD2, as well as clinically relevant mutations in the JAK-STAT pathway., Enteropathy-associated T cell lymphoma (EATL) is a lethal, and the most common, neoplastic complication of celiac disease. Here, we defined the genetic landscape of EATL through whole-exome sequencing of 69 EATL tumors. SETD2 was the most frequently silenced gene in EATL (32% of cases). The JAK-STAT pathway was the most frequently mutated pathway, with frequent mutations in STAT5B as well as JAK1, JAK3, STAT3, and SOCS1. We also identified mutations in KRAS, TP53, and TERT. Type I EATL and type II EATL (monomorphic epitheliotropic intestinal T cell lymphoma) had highly overlapping genetic alterations indicating shared mechanisms underlying their pathogenesis. We modeled the effects of SETD2 loss in vivo by developing a T cell–specific knockout mouse. These mice manifested an expansion of γδ T cells, indicating novel roles for SETD2 in T cell development and lymphomagenesis. Our data render the most comprehensive genetic portrait yet of this uncommon but lethal disease and may inform future classification schemes.Item The gut microbiome, immunity, and Plasmodium severity(Elsevier, 2020-12) Waide, Morgan L.; Schmidt, Nathan W.; Pediatrics, School of MedicineMalaria continues to pose a severe threat to over half of the world's population each year. With no long-term, effective vaccine available and a growing resistance to antimalarials, there is a need for innovative methods of Plasmodium treatment. Recent evidence has pointed to a role of the composition of the gut microbiota in the severity of Plasmodium infection in both animal models and human studies. Further evidence has shown that the gut microbiota influences the adaptive immune response of the host, the arm of the immune system necessary for Plasmodium clearance, sustained Plasmodium immunity, and vaccine efficacy. Together, this illustrates the future potential of gut microbiota modulation as a novel method of preventing severe malaria.Item Impact of T Cell Dose on Outcome of T Cell-Replete HLA-Matched Allogeneic Peripheral Blood Stem Cell Transplantation(Elsevier, 2019) Saad, Ayman; Lamb, Lawrence; Wang, Tao; Hemmer, Michael T.; Spellman, Stephen; Couriel, Daniel; Alousi, Amin; Pidala, Joseph; Abdel-Azim, Hisham; Agrawal, Vaibhav; Aljurf, Mahmoud; Beitinjaneh, Amer M.; Bhatt, Vijaya Raj; Buchbinder, David; Byrne, Michael; Cahn, Jean-Yves; Cairo, Mitchell; Castillo, Paul; Chhabra, Saurabh; Diaz, Miguel Angel; Farhan, Shatha; Floisand, Yngvar; Frangoul, Hadar A.; Gadalla, Shahinaz M.; Gajewski, James; Gale, Robert Peter; Gandhi, Manish; Gergis, Usama; Hamilton, Betty Ky; Hematti, Peiman; Hildebrandt, Gerhard C.; Kamble, Rammurti T.; Kanate, Abraham S.; Khandelwal, Pooja; Lazaryn, Aleksandr; MacMillan, Margaret; Marks, David I.; Martino, Rodrigo; Mehta, Parinda A.; Nishihori, Taiga; Olsson, Richard F.; Patel, Sagar S.; Qayed, Muna; Rangarajan, Hemalatha G.; Reshef, Ran; Ringden, Olle; Savani, Bipin N.; Schouten, Harry C.; Schultz, Kirk R.; Seo, Sachiko; Shaffer, Brian C.; Solh, Melhem; Teshima, Takanori; Urbano-Ispizua, Alvaro; Verdonck, Leo F.; Vij, Ravi; Waller, Edmund K.; William, Basem; Wirk, Baldeep; Yared, Jean A.; Yu, Lolie C.; Arora, Mukta; Hashmi, Shahrukh; Medicine, School of MedicineData on whether the T cell dose of allogeneic peripheral blood stem cell (PBSC) products influences transplantation outcomes are conflicting. Using the Center for International Blood and Marrow Transplant Research database, we identified 2736 adult patients who underwent first allogeneic PBSC transplantation for acute leukemia or myelodysplastic syndrome between 2008 and 2014 using an HLA-matched sibling donor (MSD) or an 8/8-matched unrelated donor (MUD). We excluded ex vivo and in vivo T cell-depleted transplantations. Correlative analysis was performed between CD3+ T cell dose and the risk of graft-versus-host-disease (GVHD), relapse, nonrelapse mortality (NRM), disease-free survival (DFS), and overall survival (OS). Using maximum likelihood estimation, we identified CD3+ T cell dose cutoff that separated the risk of acute GVHD (aGVHD) grade II-IV in both the MSD and MUD groups. A CD3+ T cell dose cutoff of 14 × 107 cells/kg identified MSD/low CD3+ (n = 223) and MSD/high CD3+ (n = 1214), and a dose of 15 × 107 cells/kg identified MUD/low CD3+ (n = 197) and MUD/high CD3+ (n = 1102). On univariate analysis, the MSD/high CD3+ group had a higher cumulative incidence of day +100 aGVHD grade II-IV compared with the MSD/low CD3+ group (33% versus 25%; P = .009). There were no differences between the 2 groups in engraftment rate, risk of aGVHD grade III-IV or chronic GVHD (cGVHD), NRM, relapse, DFS, or OS. The MUD/high CD3+ group had a higher cumulative incidence of day +100 aGVHD grade II-IV compared with the MUD/low CD3+ group (49% versus 41%; P = .04). There were no differences between the 2 groups in engraftment rate, risk of severe aGVHD or cGVHD, NRM, relapse, DFS, or OS. Multivariate analysis of the MSD and MUD groups failed to show an association between CD3+ T cell dose and the risk of either aGVHD grade II-IV (P = .10 and .07, respectively) or cGVHD (P = .80 and .30, respectively). Subanalysis of CD4+ T cells, CD8+ T cells, and CD4+/CD8+ ratio failed to identify cutoff values predictive of transplantation outcomes; however, using the log-rank test, the sample size was suboptimal for identifying a difference at this cutoff cell dose. In this registry study, the CD3+ T cell dose of PBSC products did not influence the risk of aGVHD or cGVHD or other transplantation outcomes when using an MSD or an 8/8-matched MUD. Subset analyses of CD4+ and CD8+ T cell doses were not possible given our small sample size.Item Pharmacological inhibition of tyrosine protein-kinase 2 reduces islet inflammation and delays type 1 diabetes onset in mice(bioRxiv, 2024-05-09) Syed, Farooq; Ballew, Olivia; Lee, Chih-Chun; Rana, Jyoti; Krishnan, Preethi; Castela, Angela; Weaver, Staci A.; Chalasani, Namratha Shivani; Thomaidou, Sofia F.; Demine, Stephane; Chang, Garrick; de Brachène, Alexandra Coomans; Alvelos, Maria Ines; Marselli, Lorella; Orr, Kara; Felton, Jamie L.; Liu, Jing; Marchetti, Piero; Zaldumbide, Arnaud; Scheuner, Donalyn; Eizirik, Decio L.; Evans-Molina, Carmella; Pediatrics, School of MedicineTyrosine protein-kinase 2 (TYK2), a member of the Janus kinase family, mediates inflammatory signaling through multiple cytokines, including interferon-α (IFNα), interleukin (IL)-12, and IL-23. Missense mutations in TYK2 are associated with protection against type 1 diabetes (T1D), and inhibition of TYK2 shows promise in the management of other autoimmune conditions. Here, we evaluated the effects of specific TYK2 inhibitors (TYK2is) in pre-clinical models of T1D. First, human β cells, cadaveric donor islets, and iPSC-derived islets were treated in vitro with IFNα in combination with a small molecule TYK2i (BMS-986165 or a related molecule BMS-986202). TYK2 inhibition prevented IFNα-induced β cell HLA class I up-regulation, endoplasmic reticulum stress, and chemokine production. In co-culture studies, pre-treatment of β cells with a TYK2i prevented IFNα-induced activation of T cells targeting an epitope of insulin. In vivo administration of BMS-986202 in two mouse models of T1D (RIP-LCMV-GP mice and NOD mice) reduced systemic and tissue-localized inflammation, prevented β cell death, and delayed T1D onset. Transcriptional phenotyping of pancreatic islets, pancreatic lymph nodes (PLN), and spleen during early disease pathogenesis highlighted a role for TYK2 inhibition in modulating signaling pathways associated with inflammation, translational control, stress signaling, secretory function, immunity, and diabetes. Additionally, TYK2i treatment changed the composition of innate and adaptive immune cell populations in the blood and disease target tissues, resulting in an immune phenotype with a diminished capacity for β cell destruction. Overall, these findings indicate that TYK2i has beneficial effects in both the immune and endocrine compartments in models of T1D, thus supporting a path forward for testing TYK2 inhibitors in human T1D.Item The Role of Interleukin-10 in CD4+ T Cell-Mediated Neuroprotection after Facial Nerve Injury(2019-05) Runge, Elizabeth Marie; Jones, Kathryn J.; Block, Michelle L.; Sanders, Virginia M.; Sengelaub, Dale R.; Xu, Xiao-MingThe adaptive arm of the immune system is necessary for facial motoneuron (FMN) survival after facial nerve axotomy (FNA). CD4+ T cells mediate FMN survival after FNA in an interleukin-10 (IL-10) dependent manner, but are not themselves the cellular source of neuroprotective IL-10. The aims of this study are to elucidate the neuroprotective capacity of cell-specific IL-10 expression, and to investigate the manner in which CD4+ T cells participate in IL-10 signaling after FNA. Immunohistochemistry revealed that FMN themselves were constitutive producers of IL-10, and astrocytes were induced to make IL-10 after FNA. Il10 mRNA co-localized with microglia before and after axotomy, but microglial production of IL-10 protein was not detected. To determine whether any single source of IL-10 is critical for FMN survival, Cre/Lox mouse strains were utilized to selectively knock out IL-10 in neurons, astrocytes, and microglia. In agreement with the localization data reflecting concerted IL-10 production by multiple cell types, no single cellular source of IL-10 was necessary for FMN survival. Gene expression analysis of wild-type, immunodeficient, and immune cell-reconstituted animals was performed to determine the role of the immune system in modulating the central IL-10 signaling cascade. This revealed that CD4+ T cells were necessary for full upregulation of central IL-10 receptor (IL-10R) expression after FNA, regardless of their own IL-10R beta (IL-10RB) expression or IL-10R signaling capability. Surprisingly, the ability of CD4+ T cells to respond to IL-10 was critical for their ability to mediate neuroprotection. Adoptive transfer of IL-10RB-deficient T cells resulted in increased central expression of genes associated with microglial activation, antigen presentation, T cell co-stimulation, and complement deposition in response to injury. These data suggest that IL-10RB functions on the T cell to prevent non-neuroprotective immune activation after axotomy. The conclusions drawn from this study support a revised hypothesis for the mechanisms of IL-10-mediated neuroprotection, in which IL-10 serves both trophic and immune-modulating roles after axotomy. This research has implications for the development of immune-modifying therapies for peripheral nerve injury and motoneuron diseases.Item SOD1G93A transgenic mouse CD4+ T cells mediate neuroprotection after facial nerve axotomy when removed from a suppressive peripheral microenvironment(Elsevier B.V., 2014-08) Mesnard-Hoaglin, Nichole A.; Xin, Junping; Haulcomb, Melissa M.; Batka, Richard J.; Sanders, Virginia M.; Jones, Kathryn J.; Department of Anatomy & Cell Biology, IU School of MedicineAmyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease involving motoneuron (MN) axonal withdrawal and cell death. Previously, we established that facial MN (FMN) survival levels in the SOD1G93A transgenic mouse model of ALS are reduced and nerve regeneration is delayed, similar to immunodeficient RAG2-/- mice, after facial nerve axotomy. The objective of this study was to examine the functionality of SOD1G93A splenic microenvironment, focusing on CD4+ T cells, with regard to defects in immune-mediated neuroprotection of injured MN. We utilized the RAG2-/- and SOD1G93A mouse models, along with the facial nerve axotomy paradigm and a variety of cellular adoptive transfers, to assess immune-mediated neuroprotection of FMN survival levels. We determined that adoptively transferred SOD1G93A unfractionated splenocytes into RAG2-/- mice were unable to support FMN survival after axotomy, but that adoptive transfer of isolated SOD1G93A CD4+ T cells could. Although WT unfractionated splenocytes adoptively transferred into SOD1G93A mice were able to maintain FMN survival levels, WT CD4+ T cells alone could not. Importantly, these results suggest that SOD1G93A CD4+ T cells retain neuroprotective functionality when removed from a dysfunctional SOD1G93A peripheral splenic microenvironment. These results also indicate that the SOD1G93A central nervous system microenvironment is able to re-activate CD4+ T cells for immune-mediated neuroprotection when a permissive peripheral microenvironment exists. We hypothesize that dysfunctional SOD1G93A peripheral splenic microenvironment may compromise neuroprotective CD4+ T cell activation and/or differentiation, which, in turn, results in impaired immune-mediated neuroprotection for MN survival after peripheral axotomy in SOD1G93A mice.Item STAT6 and PARP Family Members in the Development of T Cell-dependent Allergic Inflammation(KoreaMed Synapse, 2016-08) Krishnamurthy, Purna; Kaplan, Mark H.; Department of Pediatrics, IU School of MedicineAllergic inflammation requires the orchestration of altered gene expression in the target tissue and in the infiltrating immune cells. The transcription factor STAT6 is critical in activating cytokine gene expression and cytokine signaling both in the immune cells and in target tissue cells including airway epithelia, keratinocytes and esophageal epithelial cells. STAT6 is activated by the cytokines IL-4 and IL-13 to mediate the pathogenesis of allergic disorders such as asthma, atopic dermatitis, food allergy and eosinophilic esophagitis (EoE). In this review, we summarize the role of STAT6 in allergic diseases, its interaction with the co-factor PARP14 and the molecular mechanisms by which STAT6 and PARP14 regulate gene transcription.Item The transcription factor network in Th9 cells(Springer, 2017-01) Kaplan, Mark H.; Pediatrics, School of MedicineThe development of T helper cell subsets requires activated T cells that respond to a polarizing cytokine environment resulting in the activation and expression of transcription factors. The subset-specific transcription factors bind and induce the production of specific effector cytokines. Th9 cells express IL-9 and develop in the presence of TGFβ, IL-4, and IL-2. Each of these cytokines activates signaling pathways that are required for Th9 differentiation and IL-9 production. In this review, I summarize what is currently understood about the signaling pathways and transcription factors that promote the Th9 genetic program, providing some perspective for the integration of the signals in regulating the Il9 gene and dictating the expression of other Th9-associated genes. I highlight how experiments in mouse cells have established a transcriptional network that is conserved in human T cells and set the stage toward defining the next important questions for a more detailed understanding of Th9 cell development and function.