Principal Investigator: Brian Rudd

DESCRIPTION (provided by applicant): 

A long-standing question in immunology is why some naïve CD8+ T cells become effectors and die after infection, whereas others survive to become memory cells. The current dogma suggests that a single lineage of naïve CD8+ T cells can give rise to either effector or memory T cells depending on cues they encounter (inflammation, antigen) in the priming environment during infection. However, we recently discovered that the propensity for cells to adopt particular fates during infection is linked to their development origins, i.e., whether they were derived from stem cell populations in the fetal liver or bone marrow. We found that fetal-derived CD8+ T cells are the first to respond to infection in adulthood but rapidly become short-lived effectors. In contrast, adult-derived CD8+ T cells respond with slower kinetics but give rise to more memory CD8+ T cells. An important question is, why are fetal-derived T cells the first to respond to infection in adult animals? Answering this question has been a challenge because we lack critical information on how developmental origin alters CD8+ T cell position and behavior during priming in the lymph node. To overcome this challenge, we have formed a collaboration with the Xu lab to image the behavior of live T cells throughout the entire depth of the lymph node 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 respond differently to dendritic cells (DCs) in the lymph node during priming. To differentiate between these possibilities, we will use fate-mapping ‘timestamp’ mice and high-resolution three-photon (3P) microscopy to map out the developmental layers of CD8+ T cells in the lymph node during infection. Upon completion of these studies, we expect to provide a new conceptual framework to explain why individual CD8+ T cells behave in distinct ways in the lymph node and are recruited into the response with different kinetics.