Rajat Varma, Ph.D.
Investigator
Chief, T-Cell Biophysics Unit
T-Cell Biophysics Unit
Dr. Varma received his Ph.D. in cell biology from National Center for Biological Sciences, India, where he studied the organization of GPI-anchored proteins in living cells using optical techniques such as fluorescence resonance energy transfer (FRET) microscopy. His postdoctoral training took place at the Skirball Institute for Biomolecular Medicine, NYU, where his research work focused on the relationship between T-cell receptor (TCR) triggering and signaling in micro-clusters. He joined the Laboratory of Cellular and Molecular Immunology in the winter of 2007.
Description of Research Program
The T-Cell Biophysics Unit will use multidisciplinary approaches to investigate signaling in immune cells. Specifically, we are interested in using fluorescence microscopy and spectroscopy to understand signaling events in single living T cells. We are interested in two major questions:
- What is the quantitative relationship between TCR triggering events at the cell surface and transcription factor activity?
- How is information transfer taking place between subunits of multi-subunit receptor systems such as antigen receptors and cytokine receptors?
A quantitative relationship between triggering of TCRs and activation of transcription factor molecules has not been determined. We hypothesize that a balance of transcription factor activity downstream of TCR governs T-cell differentiation and tolerance. We also speculate that the frequency of antigen encounter might govern the differential activation of transcription factors NFAT, AP-1, and NFkB and control this balance. Co-stimulatory signals and affinity of TCR may play an important role in this process. We are interested in developing optical tools to study this process in single living cells. We will address these questions in the context of an influenza model.
Interesting questions surround the biology of multi-subunit receptors. The TCR-CD3 complex, like other ITAM-containing receptors and cytokine receptors, has the feature that the ligand binding subunit (TCRab) does not have signal transducing capability; instead the signal is transduced via the associated CD3 chains. The mechanism by which this takes place is not understood. Cytokine receptors share signal transducing subunits while other receptors, such as NKG2D, may associate with multiple signal transducing subunits. We are interested in developing fluorescence techniques that will combine FRET and fluorescence correlation spectroscopy to address a spectrum of such protein-protein interactions.
Current Research Group Members
Travis Crites, Kartika Padhan, Pauline Gonnord, and Michael Maddox
Selected Publications
(View complete list in PubMed.)
Varma R. TCR triggering by the pMHC complex: valency, affinity, and dynamics. Sci Signal. 2008 May 13;1(19):pe21.
Skokos D, Shakhar G, Varma R, Waite JC, Cameron TO, Lindquist RL, Schwickert T, Nussenzweig MC, Dustin ML. Peptide-MHC potency governs dynamic interactions between T cells and dendritic cells in lymph nodes. Nat Immunol. 2007 Aug;8(8):835-44.
Sims TN, Soos TJ, Xenias HS, Dubin-Thaler B, Hofman JM, Waite J, Cameron TO, Thomas VK, Varma R, Wiggins CH, Sheetz MP, Litman DR, Dustin ML. Opposing effects of PKCtheta and WASp on symmetry breaking and relocation of the immunological synapse. Cell. 2007 May 18;129(4):773-85.
Varma R, Campi G, Yokosuka T, Saito T, Dustin ML. T-cell receptor-proximal signals are sustained in peripheral microclusters and terminated in the central supramolecular activation cluster. Immunity. 2006 Jul;25(1):117-27.
Campi G, Varma R, Dustin ML. Actin and agonist MHC-peptide complex-dependant T-cell receptor microclusters as scaffolds for signaling. J Exp Med. 2005 Oct 17;202(8):1031-6.
Heissmeyer V, Macian F, Im SH, Varma R, Feske S, Venuprasad K, Gu H, Liu YC, Dustin ML, Rao A. Calcineurin imposes T-cell unresponsiveness through targeted proteolysis of signaling proteins. Nat Immunol. 2004 Mar;5(3):255-65.