Thursday, 23rd January 2020

Signal transduction by the T-cell antigen receptor






Balbino Alarcón







Research summary:

The properties of antigen recognition by T cells are remarkable from several points of view: T cells are highly sensitive (respond to a few antigen molecules), T cells are highly specific (respond to antigen peptides that differ in only one amino acid from null peptides), and T cells present a wide dynamic range (their respond becomes often saturated only after increasing 5-8 orders of magnitude the concentration of antigen). These properties rely on the use of a receptor (the TCR) with low affinity for antigen, typically of 1-10 mM. We believe the solution to this paradox is found in the organization of the TCR in the membrane: the TCR is organized in pre-existing oligomeros of up to 20 TCR complexes before its encounter with antigen. The oligomeric organization of the TCR can endow T cells with a higher avidity for antigen and the possibility of cooperation between TCRs. Indeed, we have demonstrated that a conformational change resulting from the binding of a TCR complex to its legend is propagated to unbound TCRs. In addition, we are investigating the intramolecular mechanisms that allow the transmission of signals from the ligand-binding subunits to the cytoplasmic tails of the signal transducing subunits in the TCR. Finally, we are studying the role TC21, a member of the RRas subfamily of GTPases, in physiological processes of T and B lymphocytes such as homeostatic control of the populations, formation of the immunological synapse, thymic selection, germinal center formation, as well as in pathological processes such as formation of T and B cell lymphomas, lung and breast cancer.


TCR-triggered TC21- and RhoG-dependent T cell phagocytosis. T cells phagocytose anti-CD3-coated latex beads. Primary mouse naïve T cells were incubated with 6 m diameter fluorescent beads (shown in orange) for 30 min and stained with fluorescent phalloidin to visualize the cortical F-actin (in green). An optical section is shown to illustrate that some beads are completely internalized. A secondary Alexa 647-labeled anti-mouse Ig (shown in magenta) was added to determine if the beads were accessible or not. This enabled us to distinguish fully internalized (arrowheads) from external beads, and even to define the presence of phagocytotic cups (arrows) in which the bead is partly inaccessible to the secondary antibody.


Prevention of allergic airway disease by the small molecular weight inhibitor of the TCR-Nck interaction Ecra4h. Ecra4h inhibits infiltration of airways by inflammatory cells in ovalbumin-sensitized mice, as measured by Fluorescence Molecular Tomography using the ProSense 680 probe 24 h after exposure to an aerosol of ovalbumin. A colorimetric scale was used to quantify the degree of infiltration. The Ecra4h group was administered two doses of Ecra4h•HCl (1 mg, i.p.) at the time of immunization, while the placebo group was treated with the vehicle alone and the control group was not immunized with ovabumin. Courtesy of Dr. Pilar Martín, National Center for Cardiovascular Disesases.




Relevant publications:

  • Iborra, I., Soto, M., Stark-Aroeira, L., Castellano, E., Alarcón, B., Alonso, C., Santos, E., and Fernández-Malavé, E. (2011). H-ras and N-ras are dispensable for T-cell development and activation but critical for protective Th1 immunity. Blood 117, 5102-5111.
  • Martínez-Martin, N., Fernández-Arenas, E., Cemerski, S., Delgado, P., Turner, M., Heuser, J., Irvine, D.J., Huang, B., Bustelo, X.R., Shaw, A.S., and Alarcón, B. (2011). TCR internalization from the immunological synapse mediated by TC21- and RhoG GTPase-dependent phagocytosis. Immunity 35, 208-222.
  • Kumar, R., Ferez, M., Swamy, M., Arechaga, I., Rejas, M., Valpuesta, J.M., Schamel, W.W.A., Alarcon, B., and van Santen, H.M. (2011). Increased sensitivity of antigen-experienced T cells via enrichment for oligomeric TCR complexes. Immunity 35, 375-387.
  • Alarcón, B., Mestre, D. and Martínez-Martín, N. (2011). The Immunological Synapse: a Cause or Consequence of TCR triggering?. Immunology 133, 420-425.
  • Martín-Cófreces, N., Alarcón, B. and Sánchez-Madrid, F. (2011). Tubulin and actin interplay at the T cell and Antigen-presenting cell interface. Frontiers Immunol 2, 24.


Doctoral Theses:

Nuria Martínez Martín (2011). Caracterización de una ruta fagocítica mediada por el TCR en linfocitos T. Universidad Autónoma de Madrid. Director: Balbino Alarcón.

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