Metabolic programming and PDHK1 control CD4+ T cell subsets and inflammation.

Andrew Macintyre, PhD, directs the Immunology Unit within the Duke Regional Biocontainment Laboratory. The Macintyre lab team designs and performs assays to quantify immune reconstitution and immune responses. The lab specializes in multiplex cytokine arrays, flow cytometry, high-throughput ELISAs, qRT-PCR, and other molecular tests. 

The assays his team develops and runs support research into biodefense and critical public health challenges. Long-running collaborative projects include the evaluation of radiation countermeasures and the development of vaccines for influenza, gonorrhea, SARS-CoV2, and other pathogens.

Olga Ilkayeva, Ph.D., is the Director of the Metabolomics Core Laboratory at Duke Molecular Physiology Institute. She received her Ph.D. training in Cell Regulation from UT Southwestern Medical Center at Dallas, TX. Her postdoctoral research in the laboratory of Dr. Chris Newgard at Duke University Medical Center focused on lipid metabolism and regulation of insulin secretion. As a research scientist at the Stedman Nutrition and Metabolism Center, Dr. Ilkayeva expanded her studies to include the development of targeted mass spectrometry analyses. Currently, she works on developing and validating quantitative mass spectrometry methods used for metabolic profiling of various biological models with emphasis on diabetes, obesity, cardiovascular disease, and the role of gut microbiome in both health and disease.

Our laboratory uses genomic and pharmacological approaches to understand how tumor dependencies are shaped by cell intrinsic factors, environmental factors, and drug treatments during the dynamic process of tumor evolution. To learn more, please visit our laboratory website: https://woodlabduke.com/.

The Hale laboratory employs techniques of cellular and molecular biology to study mechanisms responsible for the generation of both normal immune responses and immune-mediated diseases. Research in the laboratory is mainly focused on inflammatory bowel disease (IBD), an immune-mediated disorder that is hypothesized to result from the abnormal immune response of a genetically susceptible host to the antigens derived from enteric bacteria. Development of optimal treatments for disease requires a detailed understanding of mechanisms of disease pathogenesis. Thus current work in the laboratory is aimed at understanding triggers of intestinal inflammation and mechanisms of inflammation-associated neoplasia, in addition to developing novel therapies for IBD treatment. Ongoing research also includes investigating mechanisms that determine the immunogenicity of oral antigens, to develop novel adjuvants for oral vaccines. This work has relevance for pathogenesis and treatment of infectious diseases affecting the gastrointestinal tract, as well as for inflammatory bowel disease.

Dr. Hale is an expert in pathologic evaluation of colitis and immunodeficiency in both humans and mice and is board-certified in Anatomic and Clinical Pathology.

My laboratory is broadly interested in how large changes in nutritional status (e.g. malnutrition or obesity) influence T cell immunity.  Malnutrition can lead to immunodeficiency and increased risk of infection, whereas obesity is associated with inflammation that promotes multiple diseases including autoimmunity, type 2 diabetes, and cardiovascular disease.  We have identified the adipocyte-secreted hormone leptin as a critical link between nutrition and immunity.  Leptin is secreted from adipocytes in proportion to adipocyte mass and is therefore decreased in malnutrition and increased in obesity.  We have found that leptin is a critical regulator of effector T cell glucose metabolism and thereby drives effector T cell activation.  From these initial findings, we have established further lines of investigation, as summarized here.

(1) Determining molecular mechanisms of T cell dysfunction in malnutrition – Our goal is to identify metabolic and epigenetic mechanisms by which malnutrition and decreased leptin alter T cell function leading to increased susceptibility to infection and protection against autoimmune diseases.  We study this using a mouse model of autoimmunity, experimental autoimmune encephalomyelitis (EAE).

(2) Elucidating mechanisms of T cell inflammation in obesity-induced type 2 diabetes – Our goal is to identify molecular and metabolic mechanisms by which obesity alters the Teff/Treg balance, resulting in inflammation and subsequent insulin resistance leading to type 2 diabetes.  With our collaborators from UNC Chapel Hill, we are also identifying immunometabolic changes in obese animals and humans that correlate with increased susceptibility to influenza.

(3) Determining the role of insulin and IGF-1 in regulating T cell function and metabolism – Our goal is to identify how insulin influences both T cell glucose uptake and T cell differentiation/cytokine production and determine the role of insulin signaling in T cells in the setting of obesity-associated diabetes.  We hypothesize that insulin has a direct role in T cell function through its abiltiy to alter T cell glucose metabolism, influence T cell cytokine production, and impact the pathophysiology of obesity-associated type 2 diabetes. 

Over its 16 year history, our laboratory has investigated mechanisms of metabolic regulation and fuel homeostasis in mammalian systems. Major projects include: 1) Mechanisms involved in regulation of insulin secretion from pancreatic islet β-cells by glucose and other metabolic fuels; 2) Development of methods for protection of β-cells against immune-mediated damage; 3) Studies on spatial organization and regulation of systems controlling hepatic glucose balance; 4) Studies on the mechanisms involved in lipid-induced impairment of insulin secretion and action in diabetes.

Shinohara Lab Website

Immune responses against pathogens are essential for host protection, but excessive and uncontrolled immune reactions can lead to autoimmunity. How does our immune system keep the balance fine-tuned? This is a central question being asked in my laboratory.

The immune system needs to detect pathogens quickly and effectively. This is performed by the innate immune system, which includes cells such as macrophages and dendritic cells (DCs). Pathogens are recognized by pattern recognition receptors (PRRs) and may be cleared in the innate immune system. However, when pathogens cannot be eliminated by innate immunity, the adaptive immune system participates by exploiting the ability of T cells and B cells. The two immune systems work together not only to clear pathogens effectively but also to avoid collateral damages by our own immune responses. 

In my lab, we use mouse models for infectious and autoimmune diseases to understand the cellular and molecular mechanisms of; pathogen recognition by PRRs in macrophages and DCs, initiation of inflammatory responses in the innate immune system, and the impact of innate immune inflammation on the development and regulation of T cell-mediated adaptive immune responses. 

Several projects are ongoing in the lab. They are to study (1) the roles of PRR in EAE (an animal model of multiple sclerosis), (2) the interplay between immune cells and CNS (central nervous system)-resident cells during EAE and fungal infection, (3) protective and pathogenic mechanisms of immune cells in the lung during fungal infection and inflammation, and (4) the roles of a protein termed osteopontin (OPN), as both secreted (sOPN) and intracellular (iOPN) isoforms, in regulation of immune responses . Although we are very active in EAE to study autoimmunity, other mouse models, such as graft-versus-host disease (GvHD) is ongoing. Cell types we study are mainly DCs, macrophages, neutrophils, and T cells.