Averil Ma, MD, PhD

Molecular Regulation of Innate Immunity, Memory and Autoimmunity

Rainin Distingushed Professor, Department of Medicine
513 Parnassus Ave, S-1057, Box 451
San Francisco, CA 94143-0451

(415) 502-9405 tel
Averil.Ma@ucsf.edu

Lab website: http://gi.ucsf.edu/~malab/

Description of Research

Our laboratory is interested in three related questions: 1) how innate immunity regulates immune responses to microbial pathogens and; 2) how innate immunity regulates autoimmunity; and 3) how the longevity of lymphocytes are maintained. We are using a combination of gene targeting and biochemical approaches to answer 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 that A20 is expressed in T cells and dendritic cells, and may play critical roles in regulating immune responses and preventing autoimmunity. In addition, recent genetic studies suggest that A20 is important for regulating autoimmunity in human patients. Ongoing studies focus on the physiological targets of A20's enzymatic activity, and the roles of A20 in regulating dendritic cell activation, immune responses, and autoimmunity.

Another area of investigation in our lab is to understand how organisms maintain the proper number of lymphocytes. 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-15R a , the high affinity receptor for IL-15, we discovered that IL-15R a 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-15R a signals in supporting lymphocytes are due to innate immune cells such as dendritic cells expressing IL-15R a , 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.