Leonidas Carayannopoulos, M.D., Ph.D.

DEPARTMENT OF Internal Medicine
Keywords: lymphocyte, receptor, systems biology

Inflammatory cells react to injury (of which infection is a subset) by production of immunomodulatory cytokines, and by killing of abnormal cells. Secreted factors, such as cytokines and chemokines, serve as markers of cellular distress in areas of injury and guide much of this response. However, contact with abnormal cells fine-tunes cytokine release and triggers cytotoxicity by appropriate cell types.

Encounters between effectors and potential cellular targets results in engagement of multiple inhibitory and excitatory cell-surface receptors. This complex profile of receptor occupancies ultimately determines whether a target is killed or spared. We wish to understand the receptor-ligand interactions that constitute an excitatory profile. Specifically:

1) The NK receptor NKG2D recognizes multiple stress-induced ligands on target cells. We are exploring the roles of ligand number and binding kinetics on the ability of a distressed cell to invoke its own destruction through engagement of NKG2D on surveillant natural killer (NK) cells.

2) We have discovered an Orthopox MHC Class I-like protein (OMCP) that acts as a secreted antagonist of two contact-dependent receptors on immunocytes. These receptors and their roles in recognition of infected cells are being investigated.

3) We are using advanced bioinformatics tools to identify previously unsuspected ligands for immunocyte receptors. These methods led to the discovery of OMCP.

4) We are using functional genomics approaches under conditions of cellular stress to identify NK receptors of previously unsuspected importance.

A better understanding of the molecular players in effector-target recognition may help enable therapeutic modulation of innate immune responses.