NK cells protect hosts against viral pathogens as well as transformed cells. IL-15 is thought to play a critical role in NK cell development, and may mediate these effects through binding to its high affinity receptor, IL-15Ra. By generating and characterizing mice deficient for IL-15Ra, and analyzing radiation bone marrow chimera derived from these mice, we have obtained data suggesting that IL-15Ra plays critical roles in regulating mature NK cell homeostasis and NK cell activation, as well as NK cell development. Surprisingly, the mechanism by which IL-15Ra performs these functions may occur in a non-cell autonomous fashion, i.e., IL-15Ra expression on cells other than NK cells regulate NK cell functions. Accordingly, we propose to investigate the mechanism(s) by which IL-15Ra regulates NK cell function and development. Specifically, we will determine the roles of IL-15Ra in supporting: (1) NK cell development; (2) mature NK cell homeostasis; and (3) NK cell activation. These experiments should reveal novel insights into which cells use IL-15Ra to supports NK cells in vivo, and how IL-15Ra performs its unusual molecular function.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI059827-04
Application #
7212141
Study Section
Experimental Immunology Study Section (EI)
Program Officer
Ferguson, Stacy E
Project Start
2004-04-01
Project End
2009-03-31
Budget Start
2007-04-01
Budget End
2008-03-31
Support Year
4
Fiscal Year
2007
Total Cost
$323,212
Indirect Cost
Name
University of California San Francisco
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Ma, Averil; Koka, Rima; Burkett, Patrick (2006) Diverse functions of IL-2, IL-15, and IL-7 in lymphoid homeostasis. Annu Rev Immunol 24:657-79
Koka, Rima; Burkett, Patrick; Chien, Marcia et al. (2004) Cutting edge: murine dendritic cells require IL-15R alpha to prime NK cells. J Immunol 173:3594-8
Burkett, Patrick R; Koka, Rima; Chien, Marcia et al. (2004) Coordinate expression and trans presentation of interleukin (IL)-15Ralpha and IL-15 supports natural killer cell and memory CD8+ T cell homeostasis. J Exp Med 200:825-34