Susan K. Pierce, Ph.D.

Chief, Laboratory of Immunogenetics
Chief, Lymphocyte Activation Section

Dr. Pierce came to NIH from Northwestern University, where she was the William A. and Gayle Cook chair in the biological sciences and a biochemistry professor in the Department of Biochemistry, Molecular Biology, and Cell Biology, which she chaired from 1990 to 1993. Before coming to the NIAID intramural research program, Dr. Pierce was an NIH grant recipient for research in the area of antigen processing and presentation. She also served NIAID's intramural program as a member of the Board of Scientific Counselors and received a merit award from NIAID.

Description of Research Program

The long-standing research interests of the laboratory are in the molecular mechanisms by which B lymphocytes are activated by the binding of T-cell-dependent antigens to the clonally distributed B-cell antigen receptor (BCR).

Antigen binding to the BCR triggers both the initiation of signaling cascades and the internalization of the BCR and bound antigen into the cell. The internalized antigen is transported to intracellular compartments where the antigen is processed for presentation with the MHC class II molecules to helper T cells.

Using subcellular fractionation, electron microscopy, and chemical crosslinking techniques, we described the intracellular compartments in which peptide class II complexes are assembled and the pathway by which the BCR delivers antigen to this compartment. An important conclusion drawn from these studies is that the signaling function of the BCR regulates the antigen trafficking function. Recent studies revealed how these two functions may be coordinated, showing that BCR signaling and antigen targeting are initiated in cholesterol and sphingolipid-rich membrane microdomains, termed lipid rafts. The rafts concentrate signaling and cytoskeleton components and appear to serve as platforms for both BCR signaling and trafficking.

An exciting theme that emerged from the studies of rafts in B cells is that the access of the BCR to rafts is regulated by a variety of factors that function to regulate B-cell activation, including the developmental stage of the cell, the function of coreceptors and viral infection. Our goals are to understand the biochemical composition of rafts and the mechanism by which the BCR becomes associated with rafts following antigen binding. These studies are carried out with a view toward understanding how association with rafts can be regulated to enhance BCR signaling in the design of vaccines or to dampen signaling in the development of therapies for autoimmunity.

A model for the role of lipid rafts in the enhancement of B-cell antigen receptor (BCR) signaling by the coreceptor CD19/CD21. In resting B cells, the BCR and the CD19/CD21 coreceptor are excluded from lipid rafts that concentrate the Src-family kinase, Lyn. Co-ligation of the BCR and the CD19/CD21 complex by the binding of complement (C3d) tagged antigens (Ag) leads to partitioning of the co-ligated complex into lipid rafts and the prolonged signaling from rafts. The co-ligation of the CD19/CD21 complex with the BCR also blocks BCR internalization, prolonging the residency of the co-ligated complexes on the cell surface in rafts.

Confocal microscopy images of a B cell engaging antigen. The BCR is stained in the upper left image and the same cell is stained in the upper right with antibodies to intracellular phosphotyrosine-containing proteins as a measure of BCR signaling. The merged image, lower right, shows that following antigen binding the BCR becomes polarized to form a signaling active cap. Images are from a confocal laser scanning microscope Zeiss Axiovert LSM 510 META.

Movie of B cells encountering antigen. A movie of live B cells encountering antigen and patching and capping their BCR. The images were taken on a confocal laser scanning microscope Zeiss Axiovert LSM 510 META. View video in RealPlayer format. (Requires the latest version of RealPlayer. To download RealPlayer go to http://videocast.nih.gov/faq/realplayer.asp)

Research Group Members

From left: Shiang Jong Tzeng (Postdoctoral Fellow), Arun Gidwani (Postdoctoral Fellow), Terri Fantasia (Editorial Assistant), Susan Pierce (Chief), Pavel Tolar (Postdoctoral Fellow), Julie Kim (Biologist), Michelle Snyder (Postdoctoral Fellow), Anu Cherukuri (Postdoctoral Fellow).

Selected Publications

(Search PubMed.)

Cherukuri A, Cheng PC, Sohn HW, Pierce SK. The CD19/CD21 complex functions to prolong B cell antigen receptor signaling from lipid rafts. Immunity. 2001. 14: 169.

Stoddart A, Dykstra ML, Brown BK, Song W, Pierce SK, Brodsky FM. Lipid rafts unite signaling cascades with clathrin to regulate BCR internalization. Immunity. 2002. 17: 451.

Sohn HW, Gu H, Pierce SK. Cbl-b negatively regulates BCR signaling in mature B cells through ubiquitination of the tyrosine kinase Syk. J. Ex. Med. 2003. 197, 1511.

Dykstra ML, Cherukuri A, Sohn HW, Tzeng S-J, Pierce SK. Location is everything: lipid rafts and immune cell signaling. Ann Rev Immunol. 2003. 21: 457.

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