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 influenza A, which targets epithelial cells in the lungs. Receptors for TSLP are not only expressed by CD8 T cells but also dendritic cells and CD4 T 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 during influenza virus infection and examine TSLP receptor expression on anti-viral 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 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.
In Aim 3 we will perform adoptive transfers to determine how TSLP influences the type and quality of help CD4 T cells provide to CD8 T cells and how these alterations affect memory development and the maintenance of tissue-specific memory CD8 T cells. 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 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. Public Health Relevance: Immunological memory is the basis of a successful vaccine as it ensures rapid clearance of the identical pathogen following a secondary encounter. 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. Understanding and exploiting the factors regulating memory is paramount to developing vaccines with improved efficacy.
Immunological memory is the basis of a successful vaccine as it ensures rapid clearance of the identical pathogen following a secondary encounter. The goal of this proposal is to determine how a specific molecule, Thymic Stromal Lymphopoietin (TSLP), influences both the generation and long-term survivalof memory cells. Understanding and exploiting the factors regulating memory is paramount to developing vaccines with improved efficacy.
|Shane, Hillary L; Reagin, Katie L; Klonowski, Kimberly D (2018) The Respiratory Environment Diverts the Development of Antiviral Memory CD8 T Cells. J Immunol 200:3752-3761|
|Smigiel, Kate S; Richards, Elizabeth; Srivastava, Shivani et al. (2014) CCR7 provides localized access to IL-2 and defines homeostatically distinct regulatory T cell subsets. J Exp Med 211:121-36|
|Shane, Hillary L; Klonowski, Kimberly D (2014) Every breath you take: the impact of environment on resident memory CD8 T cells in the lung. Front Immunol 5:320|
|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|
|Verbist, Katherine C; Klonowski, Kimberly D (2012) Functions of IL-15 in anti-viral immunity: multiplicity and variety. Cytokine 59:467-78|
|Verbist, Katherine C; Rose, David L; Cole, Charles J et al. (2012) IL-15 participates in the respiratory innate immune response to influenza virus infection. PLoS One 7:e37539|
|Verbist, Katherine C; Field, Mary B; Klonowski, Kimberly D (2011) Cutting edge: IL-15-independent maintenance of mucosally generated memory CD8 T cells. J Immunol 186:6667-71|
|Verbist, Katherine C; Cole, Charles J; Field, Mary B et al. (2011) A role for IL-15 in the migration of effector CD8 T cells to the lung airways following influenza infection. J Immunol 186:174-82|