Natural killer (NK) cells are key players in innate immunity and are responsible for early defense against intracellular bacteria, viruses, and tumors. They function by recognition and lysis of infected cells or abnormal cells that have undergone transformation. Recognition involves at least three families of receptors unrelated to the T-cell receptor, NKG2, KIR, and NCR, which recognize classic MHC Class I molecules or stress response MHC I proteins, such as MICA/MICB, as well as microbial antigens. How lysis takes place upon receptor/ligand recognition is still unresolved, however.
All NK antigen receptors defined thus far have no intrinsic kinase activity and require linkage with adaptor proteins, such as DAP10 and DAP12, to trigger signal cascades that drive the lytic process. Recently, the researchers of Dr. Djeu's laboratory identified a specific Syk-PI3K-Rac-PAK-MEK-ERK signal cascade triggered by target ligation in human NK cells that mobilizes lytic granules to the site of contact of target cells. The membrane-proximal signals that lead to this pathway are now being investigated. The hypothesis is that both DAP 10 and DAP12 are linked to this pathway, and that DAP 10 enters via its PI3K binding site and DAP12 via its ITAM association with Syk. How these two adaptors become phosphorylated to create binding sites for PI3K and Syk is unknown, however. On the basis of data suggesting that separate Src kinases, such as Fyn, Lck, and Lyn, may be involved, the researchers are attempting to define the mechanism of these Src kinases in the early events of signal transduction leading to PI3K or Syk activation that triggers lysis in NK cells. Furthermore, they are defining the NK receptors that are responsible for the constitutive activation of lytic function in the NK cells of patients with large granular lymphocyte leukemia.
Another key mechanism by which NK cells bridge innate immunity to adaptive immunity is by production of cytokines. The researchers in our laboratory are in the process of defining whether certain NK receptors are associated with release of T helper 1-type cytokines while others might preferentially induce T helper 2-type cytokines from NK cells.