During an acute infection, activated CD8 T cells undergo a process of differentiation from naïve to cytotoxic effector cells and finally to antigen experienced memory cells. During a chronic infection, however, this process is disrupted and CD8 T cells become dysfunctional or exhausted. Exhausted cells are unable to efficiently perform effector functions and fail to acquire memory T cell properties, but it is unknown whether these defects develop progressively during chronic antigen exposure and/or if exhausted CD8 T cells undergo an irreversible fate decision early in infection. We addressed these questions by examining the memory development potential of antigen specific CD8 T cells at different stages of chronic infection. We found that virus-specific CD8 T cells removed from infection at day 30 did not have the potential to become functional memory and were physically lost upon transfer to infection-free mice. At 15 days post-infection (p.i.), antigen-specific T cells isolated from a chronic infection persisted in infection-free mice, but developed into suboptimal memory. CD8 T cells removed from chronic infection at day 8 p.i., however, retain the potential to differentiate into functional memory CD8 T cells. This progressive loss of memory potential cannot be prevented through altered priming conditions, as optimal priming by an acute infection was insufficient to prevent exhaustion. To examine the lineage origin of exhausted CD8 T cells, we tested if exhausted cells arose from the terminal effector or memory precursor subset of effector CD8 T cells. Effector subsets were sorted on day 8 of acute infection based on KLRG1 expression and transferred into chronically infected mice. Only the KLRG1lo memory precursor population gave rise to exhausted CD8 T cells, while the terminally differentiated effector CD8 T cells were not sustained. Finally, we determined how the gene expression profile of CD8 T cells is altered throughout the development of memory and exhaustion to examine the molecular basis of our cellular studies. These studies demonstrate that memory and exhaustion are distinct, that exhaustion is a progressive developmental program and that terminal differentiation and exhaustion are not part of the same lineage of differentiation.
Adviser: Jonathan Maltzman. Thesis (Ph.D. in Immunology) -- University of Pennsylvania, 2012. Includes bibliographical references.