Areas of Interest
My laboratory is broadly interested in the molecular and cell biological mechanisms used by T lymphocytes (T cells) to detect and respond to pathogens and cancers. We employ a cross-disciplinary approach centered on quantitative molecular imaging methods that integrate both light and electron microscopy.
T lymphocytes play a central role in mediating protective immunity to infections and cancers, while their aberrant function can result in chronic inflammation and autoimmunity. Two major populations of T cells are produced in the thymus: 1.) Conventional T cells express αβ T cell antigen receptors (TCR) that recognize peptide antigens associated with major histocompatibility complex molecules (pMHC), and 2.) unconventional, innate-like, T cells that express γδ TCR. γδ T cells do not undergo canonical thymic selection and therefore do not recognize pMHC antigens. The ligands and activation mechanism(s) for γδ T cells are largely unknown.
Understanding the molecular and cell biological mechanisms used by T cells to translate the detection of foreign pathogens or malignant cells (antigens) into effector responses is key to the rational design of next generation targeted cellular immunotherapies. Antigen recognition takes place at a specialized junction between T cells and antigen-presenting cells (APC), known as the immunological synapse. Here, coordinated engagement of T cell TCR, co-receptors (CD4, CD8), and costimulatory/adhesion molecules (e.g. CD28, CD2, LFA-1) initiate spatiotemporally regulated biochemical signals that lead to T cell activation . The precise mechanisms that initiate biochemical signaling of the TCR (a process known as TCR triggering), and the function of supramolecular assemblies that characterize the immunological synapse remains controversial. We and others have recently shown that pMHC-engaged TCR is released at the immunological synapse in extracellular microvesicles, by an ESCRT (endosomal sorting complex required for transport)-dependent mechanism. These TCR-containing microvesicles are transferred to partner cells across the synaptic cleft, and can induce signaling in recipient cells, pointing to a role in trans-synaptic intercellular communication. Surprisingly, HIV proteins can co-opt this process, resulting in the release of virus-like particles at the IS.
The main areas of investigation in our laboratory will include:
- Molecular mechanisms of γδ T cell antigen recognition.
- Biogenesis and function of T cell microvesicles.
- Biophysics and cell biology of triggering mechanisms of natural and synthetic antigen receptors.
Choudhuri K, Wiseman D, Brown MH, Gould K, van der Merwe PA: T-cell receptor triggering is critically dependent on the dimensions of its peptide-MHC ligand. Nature 2005, 436:578-582.
Aricescu AR*, Siebold C*, Choudhuri K, Chang VT, Lu W, Davis SJ, van der Merwe PA, Jones EY: Structure of a tyrosine phosphatase adhesive interaction reveals a spacer-clamp mechanism. Science 2007, 317:1217-1220. (Equal contributions)
Choudhuri K, van der Merwe PA: Molecular mechanisms involved in T cell receptor triggering. Semin Immunol 2007, 19:255-261. Review. Choudhuri K, Dustin ML: Signaling microdomains in T cells. FEBS Lett 2010, 584:4823-4831. Review.
Vardhana S, Choudhuri K, Varma R, Dustin ML: Essential role of ubiquitin and TSG101 protein in formation and function of the central supramolecular activation cluster. Immunity 2010, 32:531-540.
Schubert DA*, Gordo S*, Sabatino JJ, Jr., Vardhana S, Gagnon E, Sethi DK, Seth NP, Choudhuri K, Reijonen H, Nepom GT, et al.: Self-reactive human CD4 T cell clones form unusual immunological synapses. J Exp Med 2012, 209:335-352. (Equal contributions)
Cordoba SP*, Choudhuri K*, Zhang H, Bridge M, Basat AB, Dustin ML, van der Merwe PA: The large ectodomains of CD45 and CD148 regulate their segregation from and inhibition of ligated T-cell receptor. Blood 2013, 121:4295-4302. (Equal contributions)
Choudhuri K*, Llodra J*, Roth EW, Tsai J, Gordo S, Wucherpfennig KW, Kam LC, Stokes DL*, Dustin ML*: Polarized release of T-cell-receptor-enriched microvesicles at the immunological synapse. Nature 2014, 507:118-123. (Equal contributions)