Assistant Professor of Immunology
Institute of Hygiene and Applied Immunology
Center for Pathophysiology, Infectiology and Immunology
Lazarettgasse 19, 1090 Vienna, Austria
Phone: +43 (0)1 40160 - 33004
FAX: +43 (0)1 40160 - 933002
T cell antigen recognition, immunology, cell biology, signal transduction, imaging, protein engineering, biophysics, structural biology.
Imaging the molecular dynamics of T-cell antigen recognition
T-cells are remarkably sensitive towards antigen; they can detect the presence of even a single antigenic peptide/MHC complex among thousands of non-stimulatory peptide/MHC complexes on the surface of antigen-presenting cells (APCs).
Obviously, such sensitivity is critical to ensure effective immune surveillance, however, when misguided it can drive the onset of autoimmunity.
Of note, TCR-peptide/MHC interactions are only of moderate strength when measured in solution. They are 2-3 orders of magnitudes weaker than typical antibody-antigen interactions.
How can we then explain the phenomenal degree of T-cell antigen sensitivity, a hallmark of the adaptive branch of immunity?
We think that the specific microenvironment within the immunological synapse, i.e. the contact zone between the T-cell and the APC, where TCR-peptide/MHC binding takes place, provides at least in part the answer.
Binding parameters are severely influenced because receptors and ligands are pre-oriented, to some degree clustered and moreover subjected to cellular forces.
To account for these special geometrical constraints and also for the nonlinear properties of the contacting cells, we have devised a non-invasive ultrasensitive live-cell imaging approach, in which synaptic TCR-pMHC binding events are directly detected and quantified in situ.
We find TCR-binding indeed significantly increased within the synapse with both an accelerated association (about 100-fold) and, due to cellular forces, an accelerated dissociation (about 4 to12-fold).
Moreover, TCR affinities vary substantially within different synaptic regions and also between different cells. These observations imply that TCR-peptide/MHC binding and the entire process of antigen recognition are controlled through not well-understood cell-biological and cellular parameters, which could also be regulated in T-cell development, in response to environmental cues and under disease conditions. Identifying these parameters and quantifying their effects on the efficacy of T-cell antigen recognition stands in the forefront of our research.
More information about the various research projects can be found <here>
Huppa J.B. & Davis MM (2013) The interdisciplinary science of T-cell recognition. Advances in Immunology 119: 1-50
Guy C.S., Vignali K.M., Temirov J., Bettini M.L., Overacre A.E., Smeltzer M., Zhang H., Huppa J.B., Tsai Y.H., Lobry C., Xie J., Dempsey P.J., Crawford H.C., Aifantis I., Davis .M., Vignali D.A. (2013) Distinct TCR signaling pathways drive proliferation and cytokine production in T cells. Nature Immunology 14: 262-270
Xie J., Huppa J.B., Newell E.W., Huang J., Ebert P.J., Li Q.J., Davis M.M. (2012) Photocrosslinkable pMHC monomers stain T cells specifically and cause ligand-bound TCRs to be 'preferentially' transported to the cSMAC. Nature Immunology13:674-80
Huppa J.B., Axmann, M., Mörtelmaier M.A., Lillemeier B.F., Newell E.W, Brameshuber M., Klein L.O., Schütz G.J., Davis M.M. (2010) TCR-peptide-MHC interactions in situ show accelerated kinetics and increased affinity. Nature 463: 963-7
Lillemeier B.F., Mörtelmaier M.A., Forstner M.B., Huppa, J.B., Groves, J.T., Davis, M.M. (2010) TCR and LAT are expressed in separate membrane domains and concatenate during activation. Nature Immunology 11, 90-97"