Toll-like receptors (TLRs) play an essential role in host defense by activating the innate and adaptive immune system in response to invading microorganisms. These receptors evolved to detect the presence of infection through the recognition of conserved microbial products. Activation of TLRs leads to the initiation of adaptive immune responses by inducing the maturation of dendritic cells (DCs), which is required for naive T cell activation. Induction of adaptive immune responses is also controlled by regulatory T cells, which are crucial for the maintenance of peripheral T cell tolerance. In addition to inducing the upregulation of costimulatory molecules on DCs, it was recently found that signaling through TLRs also blocks the suppressive effect of regulatory T cells, which is necessary for allowing pathogen-specific responder T cells to become activated. This block of suppression was found to be dependent in part on interleukin-6 (IL-6), which is induced by TLR signaling. IL-6 was found to play a major role in making responder T cells refractory to the suppressive activity of regulatory T cells. Since the biological activities of IL-6 are mediated by the signal-transducing protein, gp130, this proposal seeks to determine if gp130 signaling pathway in T cells is critically involved in regulating suppression in vivo by generating transgenic mice in which gp130 signaling is impaired specifically in T cells. These studies would advance our understanding of the contribution of TLR-induced cytokines to the coupling of innate immune recognition and initiation of adaptive immunity in vivo.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31AI058908-03
Application #
7228078
Study Section
Special Emphasis Panel (ZRG1-IDM-L (29))
Program Officer
Hernandez, Milton J
Project Start
2005-05-01
Project End
2009-04-30
Budget Start
2007-05-01
Budget End
2008-04-30
Support Year
3
Fiscal Year
2007
Total Cost
$41,582
Indirect Cost
Name
Yale University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520