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CD4+ T lymphocytes comprise a principal component of the adaptive immune system. These cells recognize protein-derived antigens from foreign pathogens and integrate this information with contextual signals to coordinate appropriately orchestrated 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 peripheral 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 in conjunction with a variety of cellular, molecular, and genetic approaches to study CD4+ T cell tolerance in vivo in both mouse and human experimental systems. The achievement of our goals will provide a stronger foundation for understanding the initiation and progression of hyperimmune diseases and lead to the development of new therapies 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 with specificity to self-antigens. Due to their likely role in autoimmune as well as anti-tumor responses, a better understanding of the intrinsic properties of these cells should provide valuable insights into the etiology and treatment of autoimmunity and cancer. Using custom-made peptide-MHC tetramers and magnetic bead-based enrichment techniques, our lab is isolating extremely rare populations of naturally occurring self-antigen specific T cells to investigate the peripheral mechanisms of tolerance that control their activity.
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. Indeed, the failure to maintain tolerance to gut commensal microbes is thought to be an underlying cause of inflammatory bowel diseases (IBD) such as Crohn's disease and ulcerative colitis. How T cell tolerance is mediated to gut commensal antigens is unclear because there is no obvious way for these antigens to be expressed in the thymus, where central tolerance takes place. Using tetramer-based cell enrichment techniques, we are directly studying CD4+ T cell populations specific for antigens derived from commensal gut bacteria and characterizing their involvement in IBD.
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 autoimmunity and idiopathic forms of ILD. We will use peptide-MHC tetramer technology to identify and phenotype lung autoantigen-specific T cells in ILD patients and 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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