Molecular mechanisms of T cell receptor assembly and function
T cells play a fundamental role in the initiation of immune responses, and our lab seeks to understand the mechanisms of T cell recognition and function. We examine the mechanisms of T cell receptor assembly and triggering using molecular, structural and cellular approaches. Of particular interest is the role of the lipid environment in the assembly of the receptor and the initiation of signaling. We found that the T cell receptor is assembled in the cell membrane based on highly unusual protein-protein interactions, and that this mechanism is also relevant for the formation of many other activating immune receptors (1-3). In recent studies, we have examined the interaction of the cytoplasmic domains of the T cell receptor with the plasma membrane. We found that the key tyrosines of the CD3 epsilon cytoplasmic domain insert into the hydrophobic core of the lipid bilayer, meaning that the cytoplasmic domain first has to dissociate from the membrane before these tyrosines can be phosphorylated (manuscript submitted for publication). We are now studying the mechanisms that lead to dissociation of these critical cytoplasmic signaling motifs from the plasma membrane during the earliest stages of T cell activation.
Mechanisms for the development of T cell mediated autoimmune diseases
We also study the causes of T cell mediated autoimmune diseases, in particular multiple sclerosis and type 1 diabetes, in which self-reactive T cells escape negative selection in the thymus. We are exploring the mechanisms of T cell mediated autoimmunity using molecular, structural and cellular approaches and are working on novel approaches for the treatment of these diseases based on a molecular understanding of disease pathogenesis. We have found that T cell receptors do not recognize a single MHC/peptide ligand but that they can actually be activated by a number of different peptide ligands with limited sequence similarity. This finding explains why many autoimmune diseases appear to be triggered by infectious agents (4).
We recently discovered that a self-reactive TCR binds to its self-peptide/MHC complex with a highly unusual topology (5). This TCR originated from a patient with multiple sclerosis and transgenic mice that express this TCR and the corresponding human MHC molecule develop spontaneous autoimmunity in the CNS. This topology was very surprising because all previously characterized TCRs specific for microbial antigens showed a very similar binding mode. We think that the different topologies reflect distinct selection pressures: T cells with an optimal fit for microbial peptide/MHC complexes have a competitive advantage during an infection, while T cells with optimal binding properties for self-peptide/MHC complexes are most susceptible to deletion in the thymus. We are now examining how alternative topologies of TCR binding permit escape from negative selection by autoreactive T cells. Pictures that illustrate this unusual TCR topology can be viewed on our lab website at:
http://research.dfci.harvard.edu/tcell/discoveries.html
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Papers & Publications:
Call ME, Pyrdol J, Wiedmann M, Wucherpfennig KW. The organizing principle in the formation of the T cell receptor-CD3 complex. Cell 2002; 111: 967-79.
Feng J, Garrity D, Call ME, Moffett H, Wucherpfennig KW. Convergence on a distinctive assembly mechanism by unrelated families of activating immune receptors. Immunity 2005, 22: 427-38.
Call ME, Wucherpfennig KW. Common themes in the assembly and architecture of activating immune receptors. Nat. Rev. Immunol., 2007; 7: 841-50.
Wucherpfennig KW, Strominger JL. Molecular mimicry in T cell-mediated autoimmunity: Viral peptides activate human T cell clones specific for myelin basic protein. Cell 1995; 80: 695-705.
Hahn M, Nicholson MJ, Pyrdol J, Wucherpfennig KW. Unconventional topology of self-peptide/MHC binding by a human autoimmune T-cell receptor. Nat. Immunol., 2005, 6: 490-6. |
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