Integrins are critical components of the immune system through their activities in directing lymphocyte development, movement and activation. The function of the b2-integrin CD11c in vivo is largely unexplored. Our data show that CD11c is induced on primary and memory CD8 T cells responding to infection. Moreover, in the absence of CD11c, the CD8 T cell response is severely diminished indicating an integral costimulatory role for CD11c in driving CD8 T cell activation. The studies proposed here will test the hypothesis that CD11c controls CD8 T cell response by promoting T cell- DC interactions early after activation.
Three specific aims are proposed to analyze the mechanisms of CD11c costimulation:
Specific Aim 1. To determine the role of CD11c in the early CD8 T cell response to infection. Using bacterial and viral infections in conjunction with CD11c-deficient CD8 T cells, the role of CD11c in promoting proliferation, differentiation and survival of CD8 T cells will be tested.
Specific Aim 2. To analyze the role of CD11c expressed by CD8 T cells in determining the anatomy of the immune response to infection. Our preliminary results using in situ MHC class I tetramer staining identified a series of stepwise events that drive CD8 T cell activation in response to infection with Listeria monocytogenes. In situ analysis using confocal microscopy will be performed to assess the role of CD11c in activation and movement of responding endogenous and adoptively transferred CD8 T cells.
Specific Aim 3. To analyze the role of CD11c in development and function of dendritic cells. The high level expression of CD11c by DC strongly suggests an important role for CD11c in DC function. However, the analysis of CD11c-deficient DC is complicated due to the lack of a reliable marker for DC identification. We have produced transgenic mice expressing a fluorescent reporter protein under control of the CD11c promoter to circumvent this issue. These mice, when rendered CD11c-deficient, will provide the means to track and analyze CD11c-/- DC under conditions of homeostasis or infection. In sum, these studies will provide the first analysis of the role of CD11c in CD8 T cell and DC activation. PUBLIC HEALTH RELEVENCE: This proposal is focused on understanding the role of a specialized adhesion molecule, the integrin CD11c, in CD8 T cell activation in response to a bacterial infection. CD8 T cells are cytotoxic lymphocytes involved in killing of infected cells and play a central role in protection against intracellular bacterial infections. Therefore, this research has substantial impact on understanding immunity to infection and holds implications for design of effective vaccines.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI078289-05
Application #
8212137
Study Section
Immunity and Host Defense Study Section (IHD)
Program Officer
Ferguson, Stacy E
Project Start
2008-02-15
Project End
2014-01-31
Budget Start
2012-02-01
Budget End
2014-01-31
Support Year
5
Fiscal Year
2012
Total Cost
$465,254
Indirect Cost
$150,893
Name
University of Connecticut
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
022254226
City
Farmington
State
CT
Country
United States
Zip Code
06030
Bose, Tina O; Colpitts, Sara L; Pham, Quynh-Mai et al. (2014) CD11a is essential for normal development of hematopoietic intermediates. J Immunol 193:2863-72
Bose, Tina O; Pham, Quynh-Mai; Jellison, Evan R et al. (2013) CD11a regulates effector CD8 T cell differentiation and central memory development in response to infection with Listeria monocytogenes. Infect Immun 81:1140-51
Obar, Joshua J; Lefrancois, Leo (2010) Early events governing memory CD8+ T-cell differentiation. Int Immunol 22:619-25
Lefrancois, Leo; Obar, Joshua J (2010) Once a killer, always a killer: from cytotoxic T cell to memory cell. Immunol Rev 235:206-18