William E. Paul, M.D.
Chief, Laboratory of Immunology
Chief, General Immunology Section
Chief, Laboratory of Immunology, NIAID, 1970-present; Director, Office of AIDS Research, NIH, and Associate NIH Director for AIDS Research, 1994-1997
General Immunology Section
Description of Research Program
The principal topics of the group are the study of the mechanisms of action of type I cytokines, principally IL-4; study of the biologic functions of these cytokines; and investigation of the differentiation of naive T cells into cytokine-producing and memory cells.
Substantial progress has been made in clarifying the mechanisms through which the IL-4 receptor transduces the effects of the cytokine. Interaction of IL-4 with its receptor results in heterodimerization of the IL-4Ra chain and the c chain, in turn resulting in the activation of the associated kinases, Jak1 and Jak3. These kinases phosphorylate a series of conserved tyrosines in the cytosolic domain of the IL-4Ra chain. The first of these (Y497) is in a sequence highly homologous to that found in the insulin and IGF-1 receptors. When phosphorylated, it is a docking site for a series of PTB domain proteins, including IRS1/2, Shc, Dok, and the homolog of dok that we have recently described, FRIP. These substrates play a major role in regulating the growth of cells in response to IL-4; they also are important in mediating the protection from cytokine-withdrawal apoptotic death.
The second, third, and fourth tyrosines (Y575, Y603, and Y631), when phosphorylated, become docking sites for Stat6. Phosphorylated Stat6 dimerizes and is translocated to the nucleus, where it mediates many of the gene activation functions of IL-4, including determination of immunoglobulin class switching to IgE and differentiation of naive cells into TH2 cells.
The fifth conserved tyrosine (Y713) (not indicated in the illustration) is included within an ITIM and may be involved in the action of the phosphatase SHP-1, thus negatively regulating the receptor.
The members of the unit will continue to study the biochemistry of IL-4 signaling, including understanding the cross-talk between the T-cell receptor and the IL-4 receptor, and will seek evidence regarding the functional and structural organization of the cytosolic region.
A second major interest is directed an understanding the differentiation of naive CD4+ T cells into TH2 and TH1 cells. As shown in the illustration, naive T cells stimulated through their T-cell receptors and CD28 will develop into IL-4-producing (TH2) cells if they are simultaneously exposed to IL-4 for a period of 48 hours. IL-4 also suppresses the development of naive T cells into IFN(-producing (TH1) cells. These functions are dependent upon Stat6; they fail to occur in CD4+ T cells from Stat6 knockout mice.
In order to study the commitment of cells to the TH2 phenotype in greater detail and to understand the potentiality of such cells, we have recently produced a mouse in which a surrogate gene, giving rise to a protein that can be detected without perturbing the cell (enhanced green fluorescence protein [eGFP]), has replaced one of the allelic genes for IL-4. Using these mice, substantial insight is being obtained into allelic control of IL-4 expression, as well as into the capacity of various cell types to express memory for cytokine expression.
A series of studies is in progress aimed at understanding the capacity of naive cells to be primed in vitro and to study the dynamics of T-cell memory. The relative importance of cytokines and their cellular source in in vivo differentiation is under study as well as the issue of the regulation of the level of memory and of the competition between cells of the same differentiated state. These studies have the long term goal of devising strategies for maximizing T-cell memory of a given quality that may be applicable to the development of new classes of vaccines.
Awards
Texas Instruments' Foundation Founders' Prize, 3M Life Sciences Award, Tovi Comet Wallerstein Prize (Bar-Ilan University), Honorary Sc.D. (State University of New York), Abbott Laboratories Award in Clinical and Diagnostic Immunology.
Memberships
- National Academy of Sciences
- Institute of Medicine
- American Academy of Arts and Sciences
- American Association of Immunologists (former president)
- American Society for Clinical Investigation (former president)
Editorial Boards
- Immunity
- The Journal of Experimental Medicine
- Annual Review of Immunology (editor, volumes 1-17)
- Fundamental Immunology (editions 1-4)
Research Group Members
Selected Publications
(View list in PubMed.)
Grossman Z, Meier-Schellersheim M, Paul WE, Picker LJ. Pathogenesis of HIV infection: what the virus spares is as important as what it destroys. Nat Med. 2006 Mar;12(3):289-95.
Zhu J, Yamane H, Cote-Sierra J, Guo L, Paul WE. GATA-3 promotes Th2 responses through three different mechanisms: induction of
Th2 cytokine production, selective growth of Th2 cells and inhibition of Th1 cell-specific factors. Cell Res. 2006 Jan;16(1):3-10.
Guo L, Hu-Li J, Paul WE. Probabilistic regulation of IL-4 production.
J Clin Immunol. 2005 Nov;25(6):573-81.
Yamane H, Zhu J, Paul WE. Independent roles for IL-2 and GATA-3 in stimulating naive CD4+ T cells to generate a Th2-inducing cytokine environment. J Exp Med. 2005 Sep 19;202(6):793-804.
Min B, Yamane H, Hu-Li J, Paul WE. Spontaneous and homeostatic proliferation of CD4 T cells are regulated by different mechanisms.
J Immunol. 2005 May 15;174(10):6039-44.
Zhu J, Min B, Hu-Li J, Watson CJ, Grinberg A, Wang Q, Killeen N, Urban JF Jr, Guo L, Paul WE. Conditional deletion of Gata3 shows its essential function in T(H)1-T(H)2 responses. Nat Immunol. 2004 Nov;5(11):1157-65.
Interest Groups
Immunology Interest Group
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