The immune response in the liver is frequently sub-optimal. Clinical examples of this are infection with hepatitis B and C viruses, as well as tolerance to oral and alloantigens. We are interested in the fate of activated CD8+ T cells after they have entered the liver and have demonstrated that i) the liver retains activated CD8+ T cells that enter it, even in the absence of specific peptide ii) the retained cells are in physical contact with Kupffer ceils (KC) and iii) undergo apoptosis. Between events i and iii very little is known about the retained CD8+ T cells. In the preliminary data generated in the first two years of the KO8 award we show that a) activated CD8+ T cells on entering the liver undergo approximately seven fold expansion over 48 hours b) this is followed by a gradual decrease over the next 5 days due to intrahepatic apoptosis c) the presence of specific peptide results in significant reduction in the retained CD8+ T cell pool due to enhanced apoptosis d) in the absence of KC, specific peptide does not results in reduction in the activated CD8+ T cell population. These results demonstrate that KC are required for antigen induced deletion of intrahepatic activated CD8+ T cells, and are consistent with two hypothesis: Hypothesis A: Antigen presentation by KC is responsible for antigen induced deletion of intraheptic CD8+ T cells. Hypothesis B: Antigen presentation on non-KC is responsible for antigen induced deletion of intrahepatic CD8+ T cells, but KC have an important role in delivering the apoptotic signal.
Specific aim 1 : Determine if KC specific inhibition of class I MHC processing in-vivo blocks apoptosis of intrahepatic CD8+ T cells.
Specific aims 2 a) Determine if antigen presentation by KC to activated CD8+ T cells in-vitro results in CD8+ T cell apoptosis. 2b) Determine if Kupffer cell ICAM-1, CD95-L, indoleamine dioxygenase and galectin-1 are important in the firm adhesion and apoptosis of CD8+ T cells.
These aims will be achieved by using transgenic mice in which MHC class I presentation is inhibited in KC, and by developing in-vitro systems in which the role of the molecules in specific aim 2b in KC mediated apoptosis is tested.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Small Research Grants (R03)
Project #
1R03DK068135-01
Application #
6812607
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Podskalny, Judith M,
Project Start
2004-07-01
Project End
2006-06-30
Budget Start
2004-07-01
Budget End
2005-06-30
Support Year
1
Fiscal Year
2004
Total Cost
$81,750
Indirect Cost
Name
Yale University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Kuniyasu, Yuhshi; Qamar, Amir; Sheikh, Shehzad Zafar et al. (2005) Blocking intrahepatic deletion of activated CD8+ T cells by an altered peptide ligand. Cell Immunol 238:31-7