: The theme of this proposal is to understand the function of CTLA-4 (CD152) in T cell immunobiology and to elucidate the molecular mechanisms responsible for these processes. CTLA-4 is emerging as a key regulator of peripheral T cell activation and homeostasis. While it is clear that CTLA-4 ligation inhibits T cell responses, the time(s) during T cell activation and expansion and the mechanisms involved are largely unknown. The objective of this proposal is to understand when and how CTLA-4 inhibits T cell activation.
The specific aims of this proposal are: (1) to test the hypothesis that CTLA-4 ligation modulates T cell responses by increasing the 'cumulative threshold' necessary for T cell activation. We postulate that CTLA-4ligation functions to increase the 'cumulative threshold' necessary for T cell activation. Based on this hypothesis we predict that the duration of T celI-APC interaction necessary for full T cell activation is increased in the presence of CTLA-4 ligation. We will test this prediction in Aim 1. (2) to test the prediction that CTLA-4 ligation during the T-APC interaction not only regulates the magnitude of the primary T cell response, but that CTLA-4 ligation alters the ability of the T cell to respond to subsequent stimulation. We postulate that this is due to the induction of additional negative signals.
In Specific Aim 2 we will test these predictions and will test several candidate proteins as potential downstream mediators of CTLA-4 function; and (3) to elucidate protein-protein interactions involved in CTLA-4-mediated inhibition. The experimental approach is to screen for novel proteins associated with CTLA-4 cytoplasmic tail. We will test these candidate proteins in vitro and in vivo using the candidate genes identified in the 35S-labelled proteins associated with the CTLA-4cyt tail. We will also test the functional relevance of the proteins reported to bind to CTLA-4. To do this we will use RNA interference (siRNA) to specifically down modulate the expression of the candidate proteins in an inducible CTLA-4 T cell line. The insights gained from the proposed studies will permit a better definition of the mechanistic basis of the CTLA-4-mediated regulation of T cell responsiveness, T cell tolerance and loss of tolerance leading to autoimmunity. Understanding these processes is critical for designing novel therapeutic approaches for vaccine development, autoimmune disease, and in transplant and tumor immunology.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI054670-03
Application #
6874346
Study Section
Immunobiology Study Section (IMB)
Program Officer
Rathbun, Gary
Project Start
2003-04-01
Project End
2008-03-31
Budget Start
2005-04-01
Budget End
2006-03-31
Support Year
3
Fiscal Year
2005
Total Cost
$357,750
Indirect Cost
Name
University of Massachusetts Medical School Worcester
Department
Pathology
Type
Schools of Medicine
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
01655
Jain, Nitya; Nguyen, Hai; Chambers, Cynthia et al. (2010) Dual function of CTLA-4 in regulatory T cells and conventional T cells to prevent multiorgan autoimmunity. Proc Natl Acad Sci U S A 107:1524-8
Malhotra, Nidhi; Robertson, Elizabeth; Kang, Joonsoo (2010) SMAD2 is essential for TGF beta-mediated Th17 cell generation. J Biol Chem 285:29044-8
Jain, Nitya; Nguyen, Hai; Friedline, Randall H et al. (2009) Cutting edge: Dab2 is a FOXP3 target gene required for regulatory T cell function. J Immunol 183:4192-6
Friedline, Randall H; Brown, David S; Nguyen, Hai et al. (2009) CD4+ regulatory T cells require CTLA-4 for the maintenance of systemic tolerance. J Exp Med 206:421-34