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.

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 survivalof memory cells. Understanding and exploiting the factors regulating memory is paramount to developing vaccines with improved efficacy.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI081800-04
Application #
8290480
Study Section
Cellular and Molecular Immunology - A Study Section (CMIA)
Program Officer
Lapham, Cheryl K
Project Start
2009-07-25
Project End
2014-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
4
Fiscal Year
2012
Total Cost
$291,090
Indirect Cost
$95,070
Name
University of Georgia
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
004315578
City
Athens
State
GA
Country
United States
Zip Code
30602
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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; 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