Lymphocyte dynamics in lymph nodes are governed by environmental GO signals and STOP signals that interact with intrinsic polarity networks in the cell. Chemokine receptors are a major class of G-protein coupled receptors and CCR7 is the most important member of this class of receptors for delivering GO signals to naive effector T cells (Teff) in secondary lymphoid tissues. Each antigen receptor can interact with a spectrum of MHC-peptide complex ligands that vary in potency and can be presented over a wide range of concentrations on varying numbers of dendritic cells to deliver STOP signals. Signaling to polarity networks is mediated in part by protein kinase C- 8 (PKC-8), which induces symmetry breaking and conversion of stable synapses to mobile kinapses. While Teff cells activate PKC-8 in response to antigen, regulatory T cells (Treg) inactivate PKC-8 in response to antigen, suggesting distinct control of polarity by TCR signals. Our hypothesis is that particular configuration of GO and STOP and Treg PKC-8 signals lead to failure of peripheral tolerance to low potency ligands that can become autoantigens in the context of tissue injury or inflammatory stimuli. First, we will determine the effect of eliminating GO signals on Teff responses to a spectrum of ligands for a well-studied T cell receptor system. Second, we will examine the structural aspects of T cell responses to high and low potency ligands and quantify the impact of antigen presenting dendritic cell frequency on tolerance induction. Third, we will investigate the role of PKC-8 in control of Treg interactions with DC and Teff in vivo and in vitro. The results of these studies will fill major gaps in our understanding of how Teff and Treg interactions are regulated in lymph nodes and at effector sites, which is key maintaining peripheral tolerance and preventing autoimmunity.

Public Health Relevance

Vaccination strategies depend upon a physical embrace between antigen specific T lymphocytes and antigen presenting dendritic cells. We hypothesize that the stability of this embrace will depend upon the quality of antigen that defines a stop signal for the migrating T cell, signals in the environment that provide a competing go signal to the lymphocyte and polarity networks controlled by kinases. We propose experiments to determine the roles of chemokines, dendritic cell frequency and regulatory T cell protein kinase C-8 in tolerance induction.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI055037-09
Application #
8414880
Study Section
Special Emphasis Panel (ZRG1-IMM-F (02))
Program Officer
Lapham, Cheryl K
Project Start
2003-08-01
Project End
2014-12-31
Budget Start
2013-01-01
Budget End
2013-12-31
Support Year
9
Fiscal Year
2013
Total Cost
$352,000
Indirect Cost
$128,423
Name
New York University
Department
Pathology
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
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