Date(s) - 04/25/2017
4:00 pm - 5:00 pm
416 Dougherty Engineering Building
Matthew Lang grew up in Pittsburgh, PA. As an undergraduate he studied Chemistry at the University of Rochester earning a BS. He received his PhD in Physical Chemistry from the University of Chicago under the guidance of Graham Fleming where he studied ultrafast salvation dynamics and primary energy transfer steps in photosynthesis. Lang went on to study Biophysics with Steve Block at Princeton and followed the lab to Stanford University where he was a Jane Coffin Childs postdoc. In 2002, Lang moved to Boston, Massachusetts, and launched his independent academic career at MIT in the department of Mechanical Engineering and the Division of Biological Engineering. He moved to Nashville, Tennessee, in 2010 where he joined the faculty of the Department of Chemical and Biomolecular engineering at Vanderbilt University. He is also affiliated with the Department of Molecular Physiology and Biophysics at Vanderbilt University Medical School. The Lang lab focus surrounds the study of molecular and cellular machinery in particular ClpXP, kinesins, and T-cell receptors. The lab is equipped with single molecule biophysics tools including optical tweezers and single molecule fluorescence and has advanced a number of technical methods in these areas.
Mechanosensing drives αβ T cell recognition
The heterodimeric T cell receptor (TCR) recognizes foreign peptides bound to major histocompatability molecules (pMHC) on altered cells with exquisite specificity driven through physical forces generated during immune surveillance. How T cells are able to detect as few as 10 molecules displayed on an antigen presetting cell among a sea of 100,000 self peptides presents a paradox given the often undetectable binding of peptides in solution. Using optical tweezers, we developed single molecule and single molecule on single cell assays to demonstrate force driven bond strengthening and conformational change in the TCR that leads to sustained binding for strong agonists and release for irrelevant/null peptides. A conserved insert within mammalian TCRs known as the FG loop allosterically controls the bond strength. The conformational transition in both the pre-T cell receptor (preTCR) and TCR has been found to be reversible and exhibits a magnitude that correlates with ligand potency. Individual T cells can be reliably triggered with force applied through a bead with as few as two peptide molecules at the interacting surface. Our measurements are consistent with a sustained motor driven force-mediated model for signaling in direct contrast to force free, equilibrium serial engagement models.