CD4+ T cell Tolerance

CD4+ T lymphocytes comprise a principal component of the adaptive immune system. These cells recognize processed antigens derived from foreign or self proteins and integrate this information with contextual signals from the innate immune system 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 the Moon Laboratory 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 underlying causes of autoimmune, autoinflammatory, and allergic diseases, respectively.

We have found that deletional tolerance to many tissue-restricted self antigens is minimal and that the peripheral T cell repertoire is populated by numerous potentially autoreactive T cells. Our primary aim is to understand the roles that overlapping mechanisms of peripheral tolerance play in preventing autoreactive responses by these T cells in the steady state. To this end, our lab designs and utilizes state-of-the-art peptide:MHC multimer reagents in conjunction with a variety of cellular, molecular, genetic, and systems-based approaches to directly study self antigen-specific populations of CD4+ T cells from both mouse and human in vivo experimental systems.

A second major research effort is centered on the investigation of T cell tolerance to commensal microbiota of the gastrointestinal tract, which is thought to play a critical role in preventing inflammatory bowel diseases. Due to the lack of a central tolerance mechanism for these gut lumenal antigens, there is a profound absence of corresponding deletional T cell tolerance. Our aim is to directly characterize populations of CD4+ T cells with specificity for gut commensal bacteria to determine if steady state peripheral tolerance to these organisms exists, and if so, how immune recognition of commensal and pathogenic strains of enteric bacteria is distinguished.

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 strategies of treatment and prevention.