Imaging the Developmental Layers of T Cells in the Lymph Node
Principal Investigator: Brian Rudd
DESCRIPTION (provided by applicant):
One of the most enduring mysteries in immunology is why some naïve T cells become effectors and die after infection, whereas others survive and become memory cells. The current dogma suggests that a single lineage of naïve T cells can give rise to either effector or memory T cells, depending upon cues (inflammation, antigen) they encounter in the priming environment during infection. However, we recently discovered that the propensity to adopt particular fates during infection is actually determined prior to infection and linked to when T cells were initially created in the host. We made this discovery using our innovative fate mapping system, which ‘timestamps’ T cells produced at various stages of life. We found that T cells made near birth are rapidly recruited into the response and become short-lived effectors, whereas those made later in life respond more slowly and preferentially become memory T cells. An important and unanswered question is why fetal-derived T cells are the first to respond to infection in adult animals. The goal of this pilot project is to combine the immunological models in the Rudd lab, the imaging experience in the Fowell lab, and the technological tools in the Xu lab to understand how the ontogeny of T cells is linked to their location and dynamics in the lymph nodes during infection. Our hypothesis is that fetal-derived cells are the first to respond to infection in adulthood either (a) because they are optimally positioned in the lymph node prior to infection, or (b) because they are better at ‘hunting’ antigen-presenting cells in the lymph node during early stages of infection. To differentiate between these possibilities, we will use high-resolution three-photon (3P) microscopy to map out the developmental layers of CD8+ T cells in the lymph node during infection. These studies will add an entirely new dimension (development) and cutting-edge technology (3P microscopy) to Dr. Fowell’s project, which seeks to understand how T cell microanatomical location impacts function.