Cellular and Molecular Studies of Cellular Cytotoxicity

The primary goal of our group is to achieve a more complete understanding of the cellular and molecular mechanisms of natural killer (NK) cell development and function. A large portion of modern cancer research has focused on the ability of the immune system to destroy cancer cells using tumor-specific antibodies and immunomodulatory agents. A better understanding of the mode of NK cell tumor recognition will allow us to design novel antitumor therapies.

The majority of our effort is directed toward the characterization of the murine Ly49 and human KIR families of NK cell receptors for class I MHC. Our lab has determined the organization of the Ly49 gene cluster in 129, BALB/c and NOD mice, demonstrating that Ly49 gene content and functional characteristics are significantly different between inbred mouse strains, analogous to the haplotype differences observed in the human KIR genes.

Our group has discovered a probabilistic transcriptional switch that controls Ly49 gene activation, and we have shown that the separately evolved human KIR gene family uses the same type of switch, indicating that probabilistic switches will likely be involved in many systems where genes are selectively activated in a subset of the cells in a given tissue. This discovery has important implications for the control of stem cell differentiation, and may one day allow us to modify cell fate in differentiating systems such as bone marrow cultures.

Collaborators on this research include Mary Carrington and Dan McVicar, NCI.