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Cytokines,
Ubiquitination and Immune Homeostasis
The immune system is remarkably plastic and must constantly readjust the
numbers and activation state of its cellular constituents to match the
appropriate environmental situation. Our laboratory combines gene
targeting, cellular and biochemical approaches to examine: (1) how
lymphocytes as a diffuse immune organ are maintained within an entire
organism, i.e., lymphoid homeostasis; and (2) how individual cells integrate
extracellular signals to make decisions about survival, proliferation
and activation. Two current projects in the lab include the roles
of IL-15R a in regulating memory CD8+ T cells and NK cells, and the roles
of A20 in integrating pro-inflammatory stimuli within cells.
By generating and characterizing IL-15R a deficient mice, we uncovered
essential roles for IL-15R a in multiple lymphoid cell types (Lodolce
et al, Immunity 1998). We used these mice to define essential roles
for IL-15R a in supporting CD8+ memory T cells and NK cells (Schluns et
al, JI 2001, 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 non-cell
autonomous (Lodolce J Exp Med 2001, Burkett et al, PNAS 2003, Koka et
al, J Exp Med 2003). This non-cell autonomous phenomenon may
be related to IL-15R a 's ability to present IL-15 in trans to low affinity
IL-15R b and g c receptors on lymphocytes. Ongoing studies focus
on the physiological relevance of trans-presentation in vivo, on the cell
biological mechanisms by which IL-15R a trans-presentation of IL-15 may
occur, why such a novel mechanism should exist for IL-15R a , and the
varied immunological consequences of this unique cytokine biology upon
lymphocyte function.
Tumor necrosis factor (TNF) is a pleiotropic pro-inflammatory cytokine
which stimulates multiple cellular activation and survival signaling pathways.
By targeting the TNF induced A20 gene, we found that A20 deficient mice
develop profound autoimmunity coupled with an inability of A20 deficient
ceTNF induced A20 gene, we found that A20 deficient mice develop profound
autoimmunity coupled with an inability of A20 deficient cells to terminate
TNF induced NF- k B responses (Lee et al, Science 2000). To understand
A20's roles in TNF independent signals, we generated A20 TNF and A20 TNFR
double mutant mice, and found that A20 is critical for regulating toll-like
receptor (TLR) induced NF k B signals that trigger both innate and adaptive
immune responses. Moreover, we have found that A20, induced by NF
k B, is also critical for terminating JNK signals. Thus, A20 mediates
cross-talk between NF k B and JNK signaling pathways. Ongoing studies
focus on the cell biological mechanisms by which A20 and related proteins
perform these critical functions-including novel mechanisms regulating
ubiquitin conjugation.
Selected Publications:
Lodolce JP, Boone DL, Dassopoulos T, Chai S, Swain RE, Trettin S, and
Ma A. 1998. Interleukin-15 receptor maintains lymphoid homeostasis
by supporting lymphocyte homing and proliferation. Immunity 9 ; 669-676.
Ma, A, Boone, DL, and Lodolce, JP. 2000. Pleiotropic functions
of IL-15: Not so IL-2 like after all. J Exp Med 191 ;753-755.
Lee EG, Boone DL, Libby S, Chai S, Chien M, Lodolce JP, and Ma A.
2000. Failure to regulate TNF induced NF- k B and cell death responses
in A20 deficient mice. Science 289 ;2350-2354.
Lodolce JP, Burkett P, Boone DL, Chien M, Chai S, and Ma A. 2001.
T cell independent IL-15R a signals are required for bystander T cell
responses. J Exp Med 194 ;1187-94.
Burkett P, Boone DL, Koka R, Lodolce JP, Chien M, Chan F, Madonia M, and
Ma A. 2003. IL-15R a expression on CD8+ T cells is dispensable
for T cell memory. Proc Natl Acad Sci USA 100;4724-4729.
Koka R, Burkett P, Boone DL, Lodolce JP, Chien M, Chan F, and Ma A.
2003. IL-15R a deficient NK cells survive in normal but not IL-15R
a deficient mice. J Exp Med 197 ;977-984.
Wertz IE, O'Rourke KM, Zhou H, Eby M, Aravind L, Seshagiri S, Wu P, Wiesmann
C, Baker R, Boone DL, Ma A, Koonin EV, Dixit VM. De-ubiquitination
and ubiquitin ligase domains of A20 downregulate NF-kappaB signalling.
Nature (in press).
Boone DL, Turer EE, Lee EG, Ahmad RC, Wheeler MT, Tsui C, Hurley P, Chien
M, Chai S, Hitotsumatsu O, McNally E, Pickart C, and Ma A. The Ubiquitin
Modifiying Enzyme A20 is Essential for Terminating TLR Signaling. Nat
Immunol (in press).
Contact Information:
Email: ama1@itsa.ucsf.edu
Phone: 415/502-9405
Address: Box 0451, Room S 1057
The University of California, San Francisco, CA 94143, (415) 476-9000
Copyright 2003, The Regents of the University of California.
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