Thymic Stromal Lymphopoietin (TSLP) is a recently described cytokine which shares a receptor component (IL-7Ra) and significant biological redundancy with Interleukin-7. TSLP is predominately expressed by mucosal epithelial cells, which positions TSLP to play a role in orchestrating immune responses during infection with oral pathogens, including L. monocytogenes. Receptors for TSLP are not only expressed by CD8 T cells but also by dendritic cells which actively participate in shaping the generation of CD8 T cell memory. The goal of this proposal is to understand how TSLP both directly and indirectly affects the formation and maintenance of CD8 T cell memory.
In Aim 1 we will study the kinetics of TSLP expression during oral L. monocytogenes infection and examine TSLP receptor expression on anti-bacterial CD8 T cells. We will use transgenic animals to modulate either TSLP or TSLP receptor expression to determine how the cytokine directly interacts with and impacts the fate of mucosal memory CD8 T cells.
In Aim 2 we will use both in vitro culture systems and genetically modified animals to determine how populations of TSLP-conditioned DCs affect CD8 T cell priming, memory development, and homeostasis during enteric infection. Together, these studies will provide a global view of how TSLP regulates multiple lineages of cells which play active roles in CD8 T cell biology and will further our understanding of mucosal memory CD8 T cell development. This in turn will help in designing novel therapeutic interventions and vaccines, particularly those aimed at boosting immune responses at mucosal surfaces.
Immunological memory at the mucosa must be carefully balanced to ensure long-term protection without excessive immune activation. The goal of this proposal is to determine how a specific molecule, Thymic Stromal Lymphopoietin (TSLP), influences both the generation and long-term survival of memory cells specific for an enteric pathogen. Understanding and exploiting the factors regulating memory is paramount to developing vaccines with improved efficacy.
|Shane, Hillary L; Klonowski, Kimberly D (2014) A direct and nonredundant role for thymic stromal lymphopoietin on antiviral CD8 T cell responses in the respiratory mucosa. J Immunol 192:2261-70|