Laboratory of James J. Moon, Ph.D.
Email: jjmoon@mgh.harvard.edu
Overview
CD4+ T lymphocytes comprise a principal component of the adaptive immune system. These T cells recognize unique protein-derived antigens from pathogens and integrate this information with contextual cues 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 orchestrators of immune function therefore makes them attractive targets for therapeutic strategies to manipulate immune responses that have gone awry.
The overall research goal of the Moon Lab is to understand how CD4+ T cells maintain immune tolerance 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 entities that continuously or routinely make contact with mucosal surfaces. Misguided immune responses to these types of antigens underlie the pathology of autoimmune, autoinflammatory, and allergic diseases, respectively.
We are investigating 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 regulating these T cells during homeostasis and disease. Our approach involves the direct identification of these T cells using custom peptide: MHCII multimer reagents in conjunction with complementary cellular, molecular, genetic, and systems-based approaches to enable studies of 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.
Research Projects
Steady State Tolerance to Self Antigens
The role of thymic negative selection, or central tolerance, in eliminating potentially autoreactive T cells from the immune system is well established. However, the peripheral T cell repertoire is still highly populated with clones that can recognize self-antigens with high affinity. While some of these cells possess a Foxp3+ regulatory T cell (Treg) phenotype, most do not and exhibit varying levels of responsiveness to antigen stimulation. 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. We are leveraging the use of custom peptide: MHCII tetramers with transgenic mouse models of tissue-restricted self antigen expression to characterize the development and function of self antigen-specific T cells at the clonal and population levels. Areas of study include TCR repertoire selection, Treg development and differentiation, cell-intrinsic programs of hyporesponsiveness, and tissue-residency.
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 environments such as the gastrointestinal tract. 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). However, the limited ability of thymic selection to shape the development of T cells with specificity to commensal microbial antigens necessitates potent and flexible peripheral mechanisms of tolerance induction. Using our tetramer-based approaches, we are directly characterizing CD4+ T cells specific for defined antigens derived from commensal gut bacteria to study their development and role in maintaining immune homeostasis. Areas of study include TCR repertoire development, Treg development and differentiation, phenotype plasticity, and trafficking.