Rajat Varma, Ph.D.
Investigator
Chief, 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 does information transfer take 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 the 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 TCR affinity 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.
Our lab will be equipped with state-of-the-art imaging systems that will include wide field and spinning disc confocal microscopy, TIRF microscopy, and fluorescence correlation spectroscopy. We are also setting up a two-camera simultaneous acquisition system that can be utilized for image correlation analysis or live FRET and fluorescence anisotropy measurements. We will use mouse models for all our experiments and have access to a range of TCR-transgenic systems.
Selected Publications
Varma R, Mayor S. GPI-anchored proteins are organized in submicron domains at the cell surface. Nature 1998;394(6695):798-801.
Lee KH, Dinner AR, Tu C, Campi G, Raychaudhuri S, Varma R, Sims TN, Burack WR, Wu H, Wang J, Kanagawa O, Markiewicz M, Allen PM, Dustin ML, Chakraborty AK, Shaw AS. The immunological synapse balances T cell receptor signaling and degradation. Science 2003; 302(5648):1218-22.
Sharma P, Varma R, Sarasij RC, Ira, Gousset K, Krishnamoorthy G, Rao M, Mayor S. Nanoscale organization of multiple GPI-anchored proteins in living cell membranes. Cell 2004;116(4):577-89.
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; 5(3):255-65.
Campi G, Varma R and Dustin ML. Actin and agonist MHC-peptide complex dependant T cell receptor microclusters as scaffolds for signaling. J Exp Med. 2005; 202(8):1031-6.
Dustin ML, Tseng SY, Varma R, Campi G. T cell-dendritic cell immunological synapses. Curr Opin Immunol. 2006, Jun 12.
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; 25(1):117-27.
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 and Dustin ML. Opposing effects of PKCq and WASp on symmetry breaking and relocation of the immunological synapse. Cell 2007;129(4):773-85.
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;8(8):835-44.
Kaizuka Y, Douglass AD, Varma R, Dustin ML, Vale RD. Mechanisms for segregating T cell receptor and adhesion molecules during immunological synapse formation in Jurkat T cells. Proc Natl Acad Sci U S A 2007, Dec 12.
Positions Available
Postdoctoral positions are available in the T-Cell Biophysics Unit. Please contact Rajat Varma (varmarajat@niaid.nih.gov) for further information.