Beth Israel Deaconess Medical Center
3 Blackfan Circle
Boston, MA 02215
Assembly and signal transduction of the T cell receptor for antigen. To examine the role of the CD3 genes in thymocyte development and in T cell function we study mice in which the CD3 genes have been eliminated by homologous recombination techniques. In addition, the mechanisms that govern expresion of the three CD3 genes in early T cells are being studied.
The gene which is aberrant in X-linked lymphoproliferative syndrome (XLP) (SAP/SH2D1A) has been cloned and its protein crystal structure solved. At least two sets of target molecules for this small SH2 domain-containing protein have been identified: one family of hematopoietic cell surface receptors, i.e. the SLAM family, and a second molecule, which is a phosphorylated adapter. A SAP-like molecule, EAT-2, has also been found to interact with this family of surface receptors. Several lines of evidence, including analyses of missense mutations in XLP patients, support the notion that SAP/SH2D1A is a natural blocker of SH2-domain dependent interactions with members of the SLAM family. However, details of its role in signaling mechanisms are yet to be unravelled. Virus infections of a mouse in which the SAP/SH2D1A gene has been disrupted suggest that EBV infection is not per se critical for the development of XLP phenotypes. It appears that the SAP/SH2D1A gene plays a more fundamental role in T cell and APC interactions by controlling the signaling of SLAM family surface receptors and through a set of adapter molecules.
Animal models of Inflammatory Bowel Disease. Three models for experimental enterocolitis are used in the lab, two are based on cell transfer technology and a third uses the IL-2null mouse crossed with the b2m null mouse. These systems permit a rapid analysis of the role of mutant T cells and the effect of specific inhibitors of T cell functions in vivo. Thus, we are able to dissect the pathways that lead to induction of colitis, which will set the stage for development of novel therapeutic agents.
Sayos J, Wu C, Morra M, Wang N, Zhang X, Allen D, van Schaik S, Notarangelo L, Geha R, Roncarolo MG, Oettgen H, de Vries JE, Aversa G and Terhorst C. The X-linked lymphoproliferative-disease gene product SAP regulates signals induced through the co-receptor SLAM. 1998. Nature 395,462-469.
Wu C, Nguyeng KB, Pien GC, Wang N, Gullo C, Howie D, Rodriguez-Sosa M, Edwards MJ, Borrow P, Satoskar AR, Sharpe AH, Biron CA andTerhorst C. SAP controls T cell responses to virus and terminal differentiation of TH2 cells. Nature Immunology, 2001 2:410-4.
de Jong Y, Abadia-Molina A, Satoskar A, Clarke K, Rietdijk S, Sahli M, ten Hove T, Mizoguchi E, Farell RJ, Metz CN, Michetti P, van Deventer SJ, David JR, Bhan AK and Terhorst C. Macrophage migration inhibitory factor produced by the innate immune system is a target for therapy in chronic murine colitis. Nature Immunology. 2001, 2, 1061-1066.
Morra M, Lu J, Poy F, Martin M, Sayos J, Calpe S, Gullo C, Howie D, Rietdijk S, Thompson AD, Coyle A, Denny C, Yaffe M, Engel P, Eck M and Terhorst C. Structural basis for the interaction between the free SH2 domain EAT-2 with SLAM receptors in hematopoietic cells. EMBO journal 2001. 20, 5840-52.
Howie D, Simarro, M, Sayos, J, M, Guirado Sancho J and Terhorst C. Molecular dissection of the signaling and co-stimulatory function of CD150 (SLAM) and its interaction with the XLP gene product SAP. Blood, 2002, 99(3)957-65.
Last Update: 1/6/2014