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CD4+ T lymphocytes comprise a principal component of the adaptive immune system. These cells recognize protein-derived antigens from pathogens and integrate this information with contextual signals to coordinate appropriate responses from all the different players of the immune system, including cytotoxic CD8+ T cells, antibody-producing B cells and inflammatory macrophages and granulocytes. The role of CD4+ T cells as central regulators of immune function therefore makes them an attractive target for immunoregulatory intervention when immune responses go awry.
The overall research goal of Dr. Moon's lab is to understand how CD4+ T cell tolerance is maintained to antigens that should not be attacked by the immune system. This includes not only self-antigens, but antigens derived from commensal microbes and environmental proteins that continuously or routinely make contact with mucosal surfaces. Undesirable immune responses to these types of antigens are the underlying causes of autoimmune, autoinflammatory and allergic diseases, respectively.
Our aim is to understand the extent to which deletional tolerance is established for CD4+ T cells with specificity to such antigens, and what overlapping roles various non-deletional mechanisms of tolerance play in suppressing these T cells in a steady state manner. Our lab designs and utilizes state-of-the-art peptide-MHC multimer reagents that are used in conjunction with a variety of cellular, molecular, genetic and systems-based approaches to study antigen-specific CD4+ T cells with exquisite precision in both mouse and human experimental systems. Achievement of our goals will further our basic understanding of the initiation and progression of hyperimmune diseases and promote the development of novel strategies to treat them.
Characterization of Self-Antigen Specific T Cells
The role of thymic negative selection, or central tolerance, in eliminating potentially autoreactive T cells from the immune system is well established. However, increasing evidence reveals that the peripheral T cell repertoire is still highly populated with cells that can recognize self-antigens with high affinity. Due to their likely role in autoimmune as well as anti-tumor responses, a better understanding of the intrinsic properties of these cells will provide valuable insights into the etiology and treatment of autoimmunity, as well as cancer. Using custom-made peptide-MHC tetramers and magnetic enrichment techniques, our lab isolates extremely rare populations of naturally occurring self-antigen specific T cells from various immune contexts to directly investigate the peripheral mechanisms of tolerance that control their activity during homeostasis and disease.
T Cell Tolerance to Commensal Microbial Antigens
The immune system must maintain tolerance to antigens derived from not only self-tissues, but also to the multitude of commensal microbes that colonize mucosal surfaces such as the gastrointestinal system. Similarities between commensal and pathogenic microbes pose a challenge for adaptive immune recognition and indeed, failure to make such distinctions are thought to be an underlying cause of inflammatory bowel diseases (IBD). Using tetramer-based and genetic approaches, we are directly studying CD4+ T cell populations specific for antigens derived from commensal gut bacteria to characterize their behavior and involvement in mouse models of colitis.
Tracking Autoimmune T Cells in Interstitial Lung Disease
Interstitial lung disease (ILD) is a broad category of disorders involving chronic inflammation and fibrosis of loose connective tissue in the lungs. Some systemic autoimmune diseases have been implicated as causes for some kinds of ILD, but the majority of cases are idiopathic. Our lab is working with clinicians to investigate the possible link between autoimmune T cells and the pathogenesis of some forms of ILD. We are using peptide-MHC tetramer technology to identify and phenotype lung autoantigen-specific T cells in ILD patients to establish important correlates of disease.
|James Moon, PhD
Center for Immunology and Inflammatory Diseases,
Massachusetts General Hospital
Assistant Professor of Medicine, Harvard Medical School
Daniel Shin, MD
Maisa Takenaka, PhD
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Our faculty at the Center for Immunology and Inflammatory Diseases at Massachusetts General Hospital leads an aggressive multi-pronged effort to unlock the mysteries of immune and inflammatory diseases and to translate findings into improved clinical care as soon as possible.