The research in immunology focuses on understanding multiple aspects of the immune system and determining the molecular and cellular mechanisms of immunopathogenesis. Work from the immunology laboratories has led to novel discoveries on basic mechanisms of innate and adaptive immune regulation and on how infectious agents communicate with and influence the host immune system. These efforts have translated to therapeutic advances directed against diseases like multiple sclerosis.
Labs in This Research Area
Mechanisms underlying sex-related differences in autoimmune disease; meningeal inflammation and how it impacts CNS degenerative disease
Mast cells are found in most tissues including the gastrointestinal tract, respiratory tract, pancreas, synovium, brain, spinal cord, and the secondary lymphoid organs. Best studied in the context of allergic disease, the widespread location of mast cells, the plethora of inflammatory mediators they produce, and their ability to directly interact with T and B cells made them good candidates for exacerbating the inflammation associated with autoimmune diseases such as diabetes, arthritis and multiple sclerosis (MS).
We have utilized KitW/Wv mice, which are mast cell deficient, to study the contribution of these cells in a rodent model of MS, Experimental autoimmune/allergic encephalomyelitis (EAE). EAE is characterized by the T cell mediated orchestration that damages myelin and myelin producing cells in the CNS leading to severe neurological deficits due to loss of normal nerve conduction. We have shown that mast cells in the meninges are activated early in this disease and promote the opening of the blood brain barrier (BBB), vasculature that is relatively impermeable and normally sequesters the CNS from the entry of inflammatory cells. Our current studies focus on understanding how these mast cells influence these events. In the process, we have established a new paradigm for the mast cell mediated inflammation of the meninges in immunity and believe this information will likely impact the understanding of other CNS diseases.
A second line of research investigates the development of mast cells from early myeloid precursors. Mast cells share a common precursor with a related cell type, basophils. While mast cells are resident in tissues and their numbers remain relatively stable, basophils are induced in high numbers in the blood only in certain infection settings. We have demonstrated the Ikaros, a transcription factor, is essential for proper mast cell development. In Ikaros deficient mice, mast cell development is aberrant and basophils predominate in the absence of inflammatory signals. We are studying the events that underlie mast cell basophil-lineage choice in development by examining the molecular targets of Ikaros and its mode of action under basal and infection conditions.
See Dr. Brown's publications on PubMed.
Contact Dr. Brown at 312-503-0108 or the lab at 312-503-1013.
Human immunology, cytolytic T lymphocytes, transcription
Our research uses a combination of cellular and molecular approaches to study the functional and clinical roles of two genes expressed “late” (3-5 days) after T cell activation: granulysin, a cytolytic and proinflammatory molecule, and KLF13, a transcription factor that regulates the expression of the chemokine RANTES. We have generated mice expressing human granulysin in order to evaluate its effects in vivo. Our current studies are aimed at understanding the complex intracellular trafficking of granulysin as well as its role in eliminating pathogens and tumor cells in vivo.
KLF13, a member of the Kruppel-like family of transcription factors, serves as a lynchpin to control the late expression of the chemokine RANTES (CCL5) in T cells. KLF13 protein levels in T cells are very tightly controlled by multiple mechanisms including:
1. Translational regulated through the 5’-untranslated region
2. miRNA regulation of the 3’ untranslated region
3. Lysosomal and proteosomal degradation
To further study the role of KLF13, we generated mice lacking KLF13. Using both cDNA microarrays and CHIP-SEQ we identified genes in resting and activated T cells whose expression is directly controlled by KLF13. For example, T cells from mice lacking KLF13 are defective in expression of the TH2 cytokines IL4, IL5, IL9, IL10, and IL21 while expression of IFNg is elevated. These mice also lack a group of thymic CD8+ memory-like cells as well as thymic iNKT cells. Understanding how transcription factors modulate gene expression has important implications for the development of new diagnostic and therapeutic agents for human disease.
For lab information and more, see Dr. Clayberger’s faculty profile.
See Dr. Clayberger's publications on PubMed.
Contact Dr. Clayberger at 312-503-0859.
Transcriptional control of Fut7 in hematopoietic cells
My laboratory is interested in transcriptional control of leukocyte traffic during inflammation and immunity. Our focus is on glycosyltransferase genes which encode enzymes which contribute to the biosynthesis of glycan ligands for selectins. Selectins are carbohydrate-binding adhesion molecules which control leukocyte recruitment during inflammation as well as homeostatic functions such as lymphocyte recirculation through secondary lymphoid organs and leukocyte traffic to bone marrow. At least four glycosyltransferases which participate in selectin ligand formation have been identified, among which the most important is an a1,3 fucosyltransferase called FucT-VII, encoded byFut7. All evidence suggests thatFut7 is dedicated to selectin ligand formation, yet the molecular genetic basis for its complex pattern of expression is poorly understood. We use molecular biologic, genetic, cell biologic, biochemical and immunological approaches to understand how T cell activation and specific cytokines control expression ofFut7 and selectin ligands in activated T cells, howFut7 gene expression is controlled in hematopoietic stems cells and developing myeloid cells, and howFut7 gene expression is controlled by both transcription factors and cis-acting genetic elements.
For lab information and more, see Dr. Kansas's faculty profile.
See Dr. Kansas's publications on PubMed.
Contact Dr. Kansas at 312-908-3237 or the lab at 312-908-3752.
Elucidation of mechanisms of pathogenesis and immune regulation of autoimmune disease, allergy and tissue/organ transplantation
The laboratory is interested in understanding the mechanisms underlying the pathogenesis and immunoregulation of T cell-mediated autoimmune diseases, allergic disease, and rejection of tissue and organ transplants. In particular, we are studying the therapeutic use of short-term administration of costimulatory molecule agonists/antagonists and specific immune tolerance induced by infusion of antigen-coupled apoptotic cells and PLG nanoparticles for the treatment of animal models of multiple sclerosis and type 1 diabetes, allergic airway disease, as well as using tolerance for specific prevention of rejection of allogeneic and xenogeneic tissue and organ transplants.
Promising Results in Early Trial of Novel MS Treatment: Listen to a Science Friday interview with Dr. Miller regarding the Phase 1 clinical trial in multiple sclerosis patients. Read the article in Science Translational Medicine Antigen-specific tolerance by autologous myelin peptide-coupled cells: a phase 1 trial in multiple sclerosis.
For lab information and more, see Dr. Miller's faculty profile.
See Dr. Miller's publications on PubMed.
Contact Dr. Miller at 312-503-7674 or the lab at 312-503-1449.
Immune regulation and vaccines
The immune system can mount a robust adaptive response following encounter with a pathogen or during the emergence of cancer. However, if an infectious microorganism or a cancer disseminates rapidly, adaptive immune response exhaust, resulting in antigen persistence and the onset of disease. Our laboratory has demonstrated various key aspects of the exhausted immune response, including the concerted role of inhibitory pathways and T regulatory cells. In addition, we have shown the fine line between immune protection and immunopathology, and our data highlight the importance of regulating helper CD4 T cell function during antigen persistence.
Overall, our main interests are vaccines and immune regulation during antigen persistence. We utilize various systems to assess immune responses (LCMV, Listeria, vaccinia, adenovirus, tumor challenge models, as well as the humanized mouse model of HIV infection and the SIV infection model in macaques). We hope that our basic immunological research can one day translate into effective treatments against cancers and chronic infections (such as HIV), which affect millions of people worldwide.
For lab information and more, see Dr. Penaloza’s faculty profile.
See Dr. Penaloza's publications on PubMed.
Contact Dr. Penaloza at 312-503-0357.
Signal transduction pathways in T cell migration, activation and autoimmunity, cytoskeletal dynamics by PAK2/PIX/GIT multi-molecular complex
Chemokine and antigen stimulation activates multiple signaling networks to reorganize cytoskeletal systems to ensure proper migration and activation of T lymphocytes. There is increasing evidence that activators and regulators of cytoskeletal systems are critical for coordinating T cell migration and activation. However, which molecular machinery links signaling inputs from various receptors to cytoskeletal system to coordinate T cell activation and migration is incompletely understood. Our long-term research goal is to define signal transduction pathways that integrate cytoskeleton and signaling network during immune cell migration and activation in normal and pathological conditions.
Our current research focuses on one of the critical signaling pathways that are activated upon T cell receptor and chemokine receptor engagement. More specifically, we are interested in the pathway that activates PAK (p21-activated kinases) and their binding partners, GIT (G protein-coupled receptor kinase-interacting target) and PIX (PAK interacting exchange factor). Although this pathway is thought to play an important role in T cell activation and cytoskeletal dynamics and eventually generate productive immune responses, the exact function and activation mechanism are not clear. To determine the role and activation mechanism of the PAK2-PIX-GIT pathway in immune system, we combine genetic, molecular, biochemical and two-photon microscopic approaches. Two main areas of our research are:
- Determining the role of GIT2 in T cell migration and effector T cell function
- Define the role of PAK2 in T cell activation and migration.
We seek to clarify the importance of the PAK2, GIT and PIX in normal T cell activation and cytoskeletal dynamics. Since aberrant signaling in T cell migration and activation in human is associated with autoimmune diseases including multiple sclerosis (MS) and rheumatoid arthritis (RA), immunodeficiency, and blood malignancy, characterization of this signaling pathway will provide novel insights into therapeutic design to treat such diseases.
See Dr. Phee's publications on PubMed.
Contact Dr. Phee at 312-503-5240 or the lab at 312-503-0357.
Antigen Presentation, T-Cell Development and Regulation, Infectious Diseases, and Autoimmune Diseases
Our lab focuses on two of the MHC class Ib molecules, H2-M3 and CD1. These molecules have unusual binding specificity for antigens that are conserved in bacteria. H2-M3 presents N-formylated peptides to cytotoxic T cells while CD1 presents lipid antigens to several distinct subsets of T cells. The high degree of conservation of these microbial antigens combined with the limited polymorphism of M3 and CD1 make these two molecules attractive targets for T-cell based vaccines against intracellular pathogens for a genetically diverse population. We have generated several animal models to examine the roles of M3 and CD1 in T cell development, autoimmune diseases, and defense against infectious agents, including Listeria monocytogenes and Mycobacterium tuberculosis. Using these model systems, we study the mechanisms that regulate the selection and in vivo function of M3-restricted and CD1-restricted T cells. Additionally, these models are used to characterize novel microbial antigens recognized by MHC class Ib-restricted T cells. Studies on this relatively uncharacterized segment of the mammalian immunologic repertoire may lead to improved methods for vaccination against infectious diseases.
For lab information and more, see Dr. Wang's faculty profile.
See Dr. Wang's publications on PubMed.
Contact Dr. Wang at 312-503-9748 or the lab at 312-503-1093.