Development of effective CD8+ T cell memory is a significant goal of vaccination. Despite efficient CD8+ T cell priming, persistent antigen presentation has been observed for weeks following clearance of acute respiratory viral infections. However little is currently known about how antigen is retained, or what the consequence of persistent antigen presentation is on the function of CD8+ memory T cells. Several studies have suggested that serial TCR stimulation may control CD8+ memory T phenotype and the quality of the memory recall response. The goal of this research proposal is to define the cells retaining and presenting persistent antigen in a novel non- infectious model, as well as understand its role in the development and maintenance of CD8+ T cell memory maintenance and recall efficacy.
Specific Aim 1 proposes to define the cellular depots of long-lived antigen. Using confocal microscopy to track labeled antigen, and CD11c-driven diptheria-toxin receptor transgenic and knockout mouse models, the role of FDC in retention of persistent antigen will be tested.
Specific Aim 2 proposes to define the cellular participants in persistent antigen presentation. Live cell sorting and co-culture with transgenic CD8+ T cells will determine which antigen presenting cells presents persistent antigen ex vivo. Adoptive transfer of naive, effector memory, and central memory T cells will define which CD8+ T cells can respond to persistent antigen presentation.
Specific Aim 3 proposes to determine the effect of persistent IC presentation on CD8+ T cell memory. Flow cytometery-based phenotypic analysis and recombinant pathogens will be used to determine the effects of persistent antigen presentation on CD8+ T cell memory development, maintenance, and recall functionality. The results of the proposed research will inform our understanding of CD8+T cell biology with direct relevance to vaccine development.
Persistent antigen presentation is a largely uncharacterized phenomenon that has been noted following both respiratory virus and malaria infection. The proposed research will inform our basic understanding of this process in development of CD8+T cell immunity, with direct relevance to effective vaccine development.
| Mehlhop-Williams, Erin R; Bevan, Michael J (2014) Memory CD8+ T cells exhibit increased antigen threshold requirements for recall proliferation. J Exp Med 211:345-56 |
