Conventional T Cell Community
Dr Dan Barber, PhD
Chief, T-Lymphocyte Biology Unit
Laboratory of Parasitic Diseases
National Institute of Allergy and Infectious Diseases
National Institutes of Health
The primary goal of the Barber laboratory is to understand the protective and pathogenic functions of Mtb-specific CD4 T cells. In particular, we have a major interest in the cell-surface inhibitory receptor PD-1. PD-1 is a co-inhibitory member of the CD28 family that plays a major role in attenuating CD4 and CD8 T-cell effector functions during chronic viral, bacterial, and fungal infections, as well as in cancer. Blockade of the PD-1 pathway has been shown to boost T-cell responses and enhance clearance of pathogens and tumors. However, inhibitory signals through PD-1 also play a major beneficial role in regulating autoreactive T-cells and sometimes are critical for preventing damaging immunopathology during infection. Our recent work has shown that, in the case of Mtb infection, the absence of PD-1 causes CD4 T-cell responses to switch from host-protective to detrimental and actually drive fatal disease. This illustrates how not only the generation but also the appropriate negative regulation of T-cell responses is critical during Mtb infection. A major goal is to characterize the mechanisms through which regulatory pathways, including PD-1, facilitate T-cell-dependent control or exacerbation of Mtb infection.
M. tuberculosis and M. avium are common causes of morbidity and mortality in HIV-infected patients due to the requirement for Th1 cells in control of mycobacterial infections, and antiretroviral therapy (ART) usually restores CD4 T-cell-dependent protective immunity. However, instead of the expected improvement in symptoms, HIV patients with co-infections sometimes experience a rapid deterioration, referred to as immune reconstitution inflammatory syndrome (IRIS), soon after initiating ART. IRIS has become a major problem in the clinical management of the HIV pandemic, and very little is understood about the mechanisms of pathology or factors determining the susceptibility to IRIS. We have developed a robust model of experimentally induced IRIS in M. avium-infected, T-cell-deficient mice. A major goal of the Barber laboratory will be to use this system to define the basic principles of IRIS, with the aim of generating hypotheses that can be tested in IRIS patients. Understanding CD4 T-cell repopulation of microbial-infected lymphopenic hosts may lead to novel therapeutic approaches that prevent IRIS and further decrease morbidity and mortality in HIV patients during ART.
Dr Andrea Cooper, PhD
Professor of Cellular Immunology
Department of Infection, Immunity and Inflammation
University of Leicester
Professor Cooper received her undergraduate degree from University College, London and her Doctoral degree from The London School of Hygiene and Tropical Medicine UK, where she investigated the interaction between macrophages and protozoan parasites of the genus Leishmania. Moving to the National Institutes of Health in Bethesda, Maryland, US she expanded her investigation of leishmaniasis to include the T cell response of patients suffering from cutaneous, mucocutaneous and visceral forms of this disease. She then moved to the Mycobacterial Research Labs at Colorado State University and began studying the protective immune response to Mycobacterium tuberculosis. Prior to her move to the University of Leicester she was at the Trudeau Institute, Inc. for 12 years where she held the E.L. Trudeau Chair which allowed her to study the cellular immune response to Mycobacterium tuberculosis. The goal of Professor Cooper’s programme at the University of Leicester is to define the factors impacting expression of immunity in the lung. The underlying themes include:
- The role of early innate events in driving coordinated immune responses.
- The role of cytokines and chemokines in initiation, expression and regulation of immunity.
- The role of lymphocyte priming, differentiation and migratory capacity in prolonged expression of immunity.
- The role of the inflamed environment in regulating the expression of immunity.
The infection model of choice is mycobacterial challenge through droplet particles to the alveolar tissue in the lung. This model uses a low dose challenge, allowing for very early immune-mediated events in the lung tissue to be dissected with regard to kinetics, location and the contribution of specific cell types to immunity. There has been a focus on the role of IL-12, IL-23 and IL-17 and the specific role of dendritic cells and lung resident innate lymphocytes in initiation and coordination of the acquired T cell response. A newer project involves examination of the role of neonatal exposure to bacterial products as a factor which impacts early responses to mycobacterial infection in the adult. These studies impact on working models of what makes individuals more susceptible to infection in the lung and also to our understanding of basic immune mechanisms.
Dr Helen Fletcher BSc PhD
Senior Lecturer in Immunology and Director, TB Centre
London School of Hygiene and Tropical Medicine, UK
Dr Fletcher gained a PhD in Medical Microbiology from the University of Leeds and became interested in tuberculosis (TB) in 1999 during her first postdoctoral position at University College London. In 2002 she moved to the Jenner Institute at the University of Oxford as an immunologist for the first-in-man trial of a new TB vaccine, MVA85A. After 10 years at the Jenner Institute she moved to the London School of Hygiene & Tropical Medicine to establish her group, based in the Immunology and Infection Department, which focuses on immune correlates and the host response to TB vaccination. In 2015 she became Director of the TB Centre: http://tb.lshtm.ac.uk/ at the London School of Hygiene & Tropical Medicine and in 2016 became co-chair of the T-cell Immunology working group for the Collaboration for TB Vaccine Discovery (CTVD) at the Bill & Melinda Gates Foundation.
Dr Delia Goletti MD, PhD
Head of the Translation Research Unit
National Institute for Infectious Disease L. Spallanzani, Rome, Italy
Dr Goletti works on tuberculosis (TB) research focusing on immune pathogenesis, TB immunodiagnostic tests, biomarkers, autophagy, and impact of Helminth infection on HIV and TB disease, impact of immune suppressive therapy on the infectious diseases development. She recently started working on the immune pathogenesis of Echinococcosis. She has ongoing collaborations with several groups worldwide (India, Africa, Europe) working on the translational aspects of TB immune assays. She collaborates with the World Health Organization (WHO) and European Respiratory Society (ERS) for the project on TB elimination in low incidence countries. She collaborates with the New Diagnostics Working Group Task Force on Tests for progression of LTBI to active disease supported by WHO and FIND. She has a European patent (N. 1723426) on an assay of immune diagnosis of tuberculosis and on the monitoring of therapy efficacy of tuberculosis. She is academic editor of Journal of Infection, BMC Infectious Diseases, PLoS ONE, Peer J, Translational Biomedicine, Autoimmune Diseases and Therapeutic Approaches. She is present in the list of the top Italian scientists from 2014.
Dr David Lewinsohn, MD, PhD
Professor, Pulmonary and Critical Care Medicine
Professor and Senior Scientist, OHSU School of Medicine
David M. Lewinsohn is a Professor of Pulmonary and Critical Care Medicine at Oregon Health & Sciences University and holds adjunct appointments in Molecular Microbiology & Immunology as well as the Vaccine and Gene Therapy Institute. Dr. Lewinsohn received his undergraduate degree from Haverford College, his MD and PhD from Stanford University School of Medicine, internal medicine training at the University of California, San Francisco, and fellowship training in Pulmonary and Critical Care Medicine at the University of Washington. Dr. Lewinsohn’s research interest is in Tuberculosis Immunology. The core research question has been that of how the immune system can find those cells harboring the intracellular bacterium. As a result, he has been particularly interested in the role of CD8+T cells in controlling infection, and in development of an improved TB vaccine. He has been particularly interested in novel types of Mtb-specific CD8+T cells that are restricted by the monomorphic(innate) HLA molecules such as HLA-E and MR1, and in the characterization of those antigens presented in the context of infection with Mtb. Dr. Lewinsohn has had a longstanding interest in immune-correlates of mycobacterial infection.
His laboratory is run jointly with Dr. Deborah Lewinsohn, who is the Division Head of Pediatric Infectious Diseases, and whose interest has been in the immunology of pediatric TB, and the mechanisms underlying the susceptibility of young children to TB.As a result, the laboratory provides a rich environment spanning basic immune mechanisms underlying the cellular immunology and cellular biology of human infection with Mtb, to translation of these observations in TB endemic regions of the world.
Dr Lewinsohn has completed a Phase I study in collaboration with Aeras to determine whether or not vaccine-induced immunity can detect the Mtb-infected cell. His research has been supported by the ALA, the NIH, Aeras, and the VA. His has also been the recipient of an NIH Bioterrorism contract to comprehensively define human CD8 epitopes in Mycobacterium tuberculosis.
Dr Robert L. Modlin, MD
Klein Professor of Dermatology
Professor of Microbiology, Immunology and Molecular Genetics
Chief of the Division of Dermatology
Vice Chair for Cutaneous Medicine and Dermatologic Research in the Department of Medicine
David Geffen School of Medicine, University of California, Los Angeles
Dr Modlin completed his undergraduate studies at Johns Hopkins University. He received his medical degree at the New York University (NYU) School of Medicine. Modlin was a pediatrics intern at NYU and a dermatology resident at Los Angeles County/University of Southern California School of Medicine. Dr. Modlin's primary research mentor is Barry R. Bloom, Ph.D. Since 1990, Dr. Modlin's interest in leprosy began during his dermatology residency at the Los Angeles County/University of Southern California Medical Center, learning from Dr. Thomas Rea. The goal of his research is using the study of leprosy as a model to learn about mechanisms of host defense in humans. Dr. Modlin’s research laboratory has made fundamental insights into T-cell subsets, cytokine patterns, antigen presentation, innate immunity and antimicrobial mechanisms in the human immune response to infection. He has been awarded three patents for this research and has published more than 180 articles, including 13 papers in Science and Nature, and 4 in Nature Medicine. The Modlin lab's manuscript identifying distinct T cell cytokine profiles in leprosy lesions has been cited more than 1,000 times. An exciting recent discovery is the elucidation of the mechanism by which vitamin D subsets contributes to innate immunity against tuberculosis in humans, providing a rationale for therapeutic intervention.
Dr Elisa Nemes
South African Tuberculosis Vaccine Initiative (SATVI)
Department of Pathology, Division of Immunology
University of Cape Town, South Africa
Dr Nemes trained (M.Sc and PhD) in T cell immunology in the context of HIV infection at the University of Modena and Reggio Emilia, Italy, and at the University of Paris VI, France. In 2008-2010 she worked as post-doctoral scientist in Cameroon, in the framework of an Italian Cooperation Program to support the startup of research projects and to reinforce the technology transfer at CIRCB (“Chantal Biya International Reference Centre for Research on HIV/AIDS Prevention and Management”), where she contributed to research projects focused on paediatric immune responses to HIV and M. tuberculosis.
Dr Nemes moved to South Africa in 2011, where she joined the South African Tuberculosis Vaccine Initiative (SATVI) at the University of Cape Town as post-doctoral scientist first, and currently as Senior Scientist. She is involved in the scientific supervision of clinical trials of new tuberculosis vaccines, development of immunodiagnostics of M. tuberculosis infection and basic immunological studies on adaptive and innate immunity to M. tuberculosis in HIV infected and uninfected children. Dr Nemes is centrally involved in collaborative projects aimed at defining immune correlates of risk of TB disease in BCG vaccinated infants and correlates of risk of BCG/TB IRIS in HIV+ children.
Dr Philana “Ling” Lin, MD, Msc
Associate Professor, Department of Pediatrics Division of Pediatric Infectious Diseases
Children’s Hospital of Pittsburgh University of Pittsburgh School of Medicine
Dr. Philana “Ling” Lin is a pediatric infectious disease physician at the Children’s Hospital of Pittsburgh of the University of Pittsburgh Medical Center. She holds affiliate/adjunct positions in the Department of Immunology, Microbiology and Molecular Genetics and Center for Vaccine Research at the University of Pittsburgh. Dr. Lin’s lab is focused on understanding the basic pathogenesis of M. tuberculosis infection as well as early predictive and immunologic factors that protect against symptomatic tuberculosis after either recent (primary active TB) or remote infection (reactivation TB). She also has specific interests in the immunologic changes that occur during HIV-TB co-infection that result in greater risk of disease.
Dr Tom H. M. Ottenhoff, MD, PhD
Professor in Immunology
Leiden University Medical Center
The scientific mission of the Ottenhoff lab is to dissect immunological and host-genetic mechanisms of protective and pathologic immunity to mycobacterial infections and related infectious diseases, in order to design more effective intervention strategies (vaccines, treatments, and diagnostics). Our research programme is in the field of human immunology, cell biology and immunogenetics of mycobacterial infectious diseases. Amongst some of our scientific contributions are the discovery of the first specific antigens for mycobacterium reactive T-cells in humans; the identification of the first Thelper-1 cells in humans; the discovery of a new human immunodeficiency due to genetic mutations in the receptor for interleukin-12; the cloning of the first monoclonal T-regulatory cells in humans; human genetic studies that identified, with excellent collaborators, multiple new genetic variants impacting on risk of tuberculosis and leprosy; (together with prof. JJ Neefjes) the identification of a new human PKB/Akt1 controlled signaling pathway, that is manipulated by Salmonella and Mtb to inhibit phagosomal-lysosomal fusion. One current focus is on the role of T cell subsets (T-helper, T-regulatory), macrophage subsets, intracellular signaling networks, cellular function and systems biology. A related, translation-oriented focus is on Mtb antigen discovery, vaccine design and biomarker discovery. We have executed several clinical phase I/IIa first in human trials with new TB vaccines. We participate in many high profile international research consortia, which include partners from EU, US and developing countries in Asia, Africa and South America. Funding mostly comes from EC, BMGF, Dutch Government and other bodies.
Dr Kevin B. Urdahl, MD, PhD
Associate Professor, Center for Infectious Disease Research
Affiliate Associate Professor, Immunology
Clinical Associate Professor, Pediatrics
University of Washington
Dr. Urdahl graduated from Concordia College (Moorhead, Minnesota), and earned an MD and a PhD in Microbiology/Immunology from the University of Minnesota. He completed a Pediatrics residency and an Infectious Diseases fellowship at Seattle Children’s Hospital, and his postdoctoral work in Immunology at the University of Washington. He started his career as a primary investigator in the Department of Pediatrics at the University of Washington before joining Seattle Biomedical Research Institute in 2010 (now the Center for Infectious Disease Research). Dr. Urdahl continues to be an attending physician in Pediatric Infectious Diseases at Seattle Children’s Hospital. Dr Urdahl co-leads the T-cell Immunology working group for the Collaboration for TB Vaccine Discovery (CTVD) at the Bill & Melinda Gates Foundation.
The Urdahl lab is interested in understanding the factors that impede T cell-mediated immune protection during persistent Mtb infection. We have recently discovered that Foxp3-expressing regulatory T cells (T regs) restrict Mtb eradication, and pathogen-specific T regs are extremely potent in mediating this activity. Even small numbers of Mtb-specific T regs delay the arrival of effector T cells in the lung, the primary site of Mtb infection, and cause an increased bacterial burden. Future research will seek to elucidate how Mtb-specific T regs are induced and to define their precise roles and activities at different stages of infection. A key question that drives these studies is whether T reg function can be safely manipulated to prevent or treat tuberculosis. We are also interested in understanding T cell subsets that promote protection against tuberculosis. Using recently developed MHC class I and II tetramers, we can monitor the function of Mtb-specific CD8+ and CD4+ T cells throughout the course of infection. We seek to determine the lineage relationships between Mtb-specific T cells with different functional capacities, including proliferation, IFN-y production, IL-17 production, and Foxp3 expression. We plan to investigate how variations in innate immune responses help shape the subsequent T cell responses to Mtb. These studies will provide insights into how long-lived populations of protective T cell subsets are induced and maintained during persistent Mtb infection, and should help to inform novel immunization strategies.