Kai W. Wucherpfennig
Department of Cancer Immunology and AIDS
Dana-Farber Cancer Research Institute
Dana Building, Room D1410
44 Binney Street, Boston, MA 02115
My laboratory works on the structural mechanisms that guide the assembly of the T cell receptor-CD3 complex and the triggering of T cell signaling. The T cell receptor plays a critical role in the initiation of immune responses by recognizing microbial peptides bound to MHC proteins. We have shown that higher-order assembly of the T cell receptor heterodimer with its three signaling dimers occurs primarily in the cell membrane, and is organized by a highly unusual set of ionizable transmembrane residues. Each of the three major assembly steps requires the interaction of a basic T cell receptor transmembrane residue with a pair of acidic residues of the interacting signaling subunit (1). Interestingly, both acidic residues are involved in the interaction with a single basic residue suggesting a novel type of interaction that may be unique to the membrane environment. We are using several different biophysical techniques to examine the specific interactions among these ionizable transmembrane residues in this unique environment. Such interactions also appear to be important for the assembly of a number of other activating receptors in the immune system, and the structural mechanisms are thus of general interest (2).
We are also working on the structural mechanisms responsible for ligand recognition by the T cell receptor, in particular in the context of autoimmune diseases. We determined the crystal structure of the first T cell receptor from a human autoimmune disease as a complex with its peptide/MHC ligand (3). This T cell receptor originated from a patient with relapsing-remitting Multiple Sclerosis (MS) and was previously shown to be responsible for a spontaneous, MS-like disease in a T cell receptor transgenic mouse model. This T cell receptor bound to its self-peptide/MHC complex in a highly unusual topology that differed substantially from the binding mode previously defined for T cell receptors specific for microbial peptides (please visit our website for pictures). We are currently examining T cell receptors from other autoimmune diseases in order to explore the range of possible topologies. We are particularly interested in how altered topology could modify the signaling function of such T cell receptors and account for the pathogenicity of such T cells in autoimmune diseases.
Call, M.E., Pyrdol, J., Wiedmann, M., and Wucherpfennig, K.W. 2002. The organizing principle in the formation of the T cell receptor-CD3 complex. Cell 111:967-979.
Feng, J., Garrity, D., Call, M.E., Moffett, H., and Wucherpfennig, K.W. 2005. Convergence on a distinctive assembly mechanism by unrelated families of activating immune receptors. Immunity 22:427-438.
Hahn, M., Nicholson, M.J., Pyrdol, J., and Wucherpfennig, K.W. 2005. Unconventional topology of self peptide-major histocompatibility complex binding by a human autoimmune T cell receptor. Nat Immunol 6:490-496.
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