Biomedical subjects

Lawren C Wu

Publications and source records attributed to Lawren C Wu.

4 recordsLinked to original sources

PubMed2003

Dynamics of cell surface molecules during T cell recognition.

Recognition of foreign antigens by T lymphocytes is a very important component of vertebrate immunity-vital to the clearance of pathogenic organisms and particular viruses and necessary, indirectly, for the production of high affinity antibodies. T cell recognition is mediated by the systematic scanning of cell surfaces by T cells, which collectively express many antigen receptors. When the appropriate antigenic peptide bound to a molecule of the major histocompatibility complex is found-even in minute quantities-a series of elaborate cell-surface molecule and internal rearrangements take place. The sequence of events and the development of techniques required to observe these events have significantly enhanced our understanding of T cell recognition and may find application in other systems of transient cell:cell interactions as well.

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PubMed2002

Two-step binding mechanism for T-cell receptor recognition of peptide MHC.

T cells probe a diverse milieu of peptides presented by molecules of the major histocompatibility complex (MHC) by using the T-cell receptor (TCR) to scan these ligands with high sensitivity and specificity. Here we describe a physical basis for this scanning process by studying the residues involved in both the initial association and the stable binding of TCR to peptide-MHC, using the well-characterized TCR and peptide-MHC pair of 2B4 and MCC-IE(k) (moth cytochrome c, residues 88 103). We show that MHC contacts dictate the initial association, guiding TCR docking in a way that is mainly independent of the peptide. Subsequently, MCC-IE(k) peptide contacts dominate stabilization, imparting specificity and influencing T-cell activation by modulating the duration of binding. This functional subdivision of the peptide-MHC ligand suggests that a two-step process for TCR recognition facilitates the efficient scanning of diverse peptide-MHC complexes on the surface of cells and also makes TCRs inherently crossreactive towards different peptides bound by the same MHC.

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PubMed2002

Imaging synapse formation during thymocyte selection: inability of CD3zeta to form a stable central accumulation during negative selection.

TCR signaling can result in cell fates ranging from activation to tolerance to apoptosis. Organization of molecules in an "immunological synapse" between mature T cells and APCs correlates with the strength of TCR signaling. To investigate synapse formation during thymic selection, we have established a reaggregate system in which molecular recruitment of GFP fusion proteins to thymocyte:stromal cell interfaces can be visualized in real time. We demonstrate that negative selection is associated with efficient conjugate formation and rapid recruitment of p56(lck) and CD3zeta to an immunological synapse. Interestingly, CD3zeta-GFP does not accumulate at the center of the synapse, as in mature T cells, but at the periphery across a wide range of ligand densities. This implicates differences in synapse geometry in initiation of alternate signals downstream of the TCR.

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PubMed2001

Costimulation and endogenous MHC ligands contribute to T cell recognition.

To initiate an immune response, key receptor-ligand pairs must cluster in "immune synapses" at the T cell-antigen-presenting cell (APC) interface. We visualized the accumulation of a major histocompatibility complex (MHC) class II molecule, I-E(k), at a T cell-B cell interface and found it was dependent on both antigen recognition and costimulation. This suggests that costimulation-driven active transport of T cell surface molecules helps to drive immunological synapse formation. Although only agonist peptide-MHC class II (agonist pMHC class II) complexes can initiate T cell activation, endogenous pMHC class II complexes also appeared to accumulate. To test this directly, we labeled a "null" pMHC class II complex and found that, although it lacked major TCR contact residues, it could be driven into the synapse in a TCR-dependent manner. Thus, low-affinity ligands can contribute to synapse formation and T cell signaling.

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