Self-ligand stimulation is essential for T cell development in the thymus and the induction of central tolerance. The importance of peripheral self-ligand stimulation, however, is only beginning to be appreciated. The preliminary data in this proposal indicates that CD4 T cells deprived of peripheral self-ligand stimulation develop a progressive defect in their ability to physically interact with dendritic cells (DCs) bearing cognate antigen. Thus, results in suboptimal T cell activation as measured by CD69 expression and in a profound defect in CD4 T cell proliferation. The central hypotheses, to be tested, are that self-ligand stimulation is essential in conditioning T cell receptivity to interaction with antigen-presenting cells (APCs) and that self-ligand deprived T cells, incapable of maintaining sustained contact with antigen-bearing APCs, follow an altered developmental pathway resulting in immunological tolerance. Tolerance will be tested using unique transplantation models and flow cytometry staining of in vivo self-ligand deprived CD4 T cells. Specifically, we will test whether self-ligand deprivation (1) impairs T cell motility within secondary lymphoid tissue and the ability of the T cell to find cognate antigen-bearing APCs, (2) impairs the ability of T cells to form transient conjugates with APCs, scan for antigens and form immunological synapses, facilitating TCR signaling, and/or (3) impairs the ability of T cells to form long-lived antigen-dependent clusters with DCs, facilitating T cell differentiation. In addition, we will explore the mechanism(s) underlying these impaired T cell-DC interactions. It is proposed that the inability of T cells to make contact, signal through the TCR and firmly adhere to cognate antigen-bearing DCs will result in inefficient activation and thus, tolerance. Understanding the mechanism of T cells interaction with cognate DCs is clearly important. It is argued that the ability to modulate T cell responses via self-ligand deprivation can have a strong impact on transplantation and autoimmunity. This proposal considers that interrupting T cell contact with peripheral self-peptide/major histocompatibility complex (MHC) molecules (self-ligands) prior to and at the time of antigen exposure may provide novel therapeutic strategies to achieve antigen-specific T cell unresponsiveness. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI069836-03
Application #
7268110
Study Section
Special Emphasis Panel (ZAI1-PA-I (M1))
Program Officer
Deckhut Augustine, Alison M
Project Start
2006-08-01
Project End
2009-07-31
Budget Start
2007-08-01
Budget End
2009-07-31
Support Year
3
Fiscal Year
2007
Total Cost
$200,754
Indirect Cost
Name
University of California San Diego
Department
Pediatrics
Type
Schools of Medicine
DUNS #
804355790
City
La Jolla
State
CA
Country
United States
Zip Code
92093
Ingulli, Elizabeth; Funatake, Castle; Jacovetty, Erica L et al. (2009) Cutting edge: antigen presentation to CD8 T cells after influenza A virus infection. J Immunol 182:29-33
Fischer, Ursula B; Jacovetty, Erica L; Medeiros, Ricardo B et al. (2007) MHC class II deprivation impairs CD4 T cell motility and responsiveness to antigen-bearing dendritic cells in vivo. Proc Natl Acad Sci U S A 104:7181-6