Our laboratory is interested in two general questions: 1) how innate immunity regulates immune responses to microbial pathogens; and 2) how memory T cells and NK cells are maintained in vivo. We are using a combination of gene targeting and biochemical approaches to answering these questions.

The critical decision point when organisms commit to inflammatory and immune responses to microbial pathogens resides in the stimulation of toll-like receptor (TLR) signals on dendritic cells. Our laboratory’s interest in this area has focused on the intracellular mechanisms by which TLR induced signal transduction events are regulated. In particular, by targeting the A20 gene in mice, we have found that a novel molecule called A20 is essential for restricting both TNF and TLR induced activation signals in macrophages and dendritic cells (Lee et al, Science 2000, Boone et al, Nature Immunology 2004). We have further found that A20 is a unique ubiquitin modifying enzyme that requlates both the activity and stability of signaling proteins such as RIP and TRAF6 (Wertz et al, Nature 2004; Boone et al, Nature Immunology 2004). A20 is a biochemically unique molecule that both deactivates and degrades target proteins. Recent studies indicate A20 is expressed in T cells and dendritic cells, and may play critical roles in regulating both innate and adaptive immune responses. Ongoing studies focus on the physiological targets of A20’s enzymatic activity, and the roles of A20 in regulating dendritic and T cell activation and immune responses.

A second general area of investigation in our lab is to understand how organisms maintain memory T cells. Work in our laboratory has revealed that IL-15 signals are critical for maintaining the numbers of NK cells and memory CD8 + T cells. By generating and characterizing mice deficient for IL-15Ra, the high affinity receptor for IL-15, we discovered that IL-15Ra is critical for supporting CD8 + memory T cells proliferation and NK cell survival (Lodolce et al, Immunity 1998, Becker et al, J Exp Med 2002, Burkett et al, PNAS 2003, Koka et al, J Exp Med 2003). Surprisingly, we found that virtually all of the effects of IL-15Ra signals in supporting lymphocytes are due to innate immune cells such as dendritic cells expressing IL-15Ra, binding IL-15, and presenting IL-15 in trans to lymphocytes (Lodolce J Exp Med 2001, Burkett et al, PNAS 2003, Koka et al, J Exp Med 2003, (Burkett et al, J Exp Med 2004, Koka et al, JI 2004). Ongoing studies focus on elucidating the specific locations and cell types that trans-present IL-15 to lymphocytes, thereby supporting memory CD8 + T cell proliferation and NK cell survival.