Quality Killing

Science Signaling  27 Oct 2009:
Vol. 2, Issue 94, pp. ec344
DOI: 10.1126/scisignal.294ec344

The selectivity and efficiency of cytotoxic T cell (CTL)–mediated killing is due to the formation of an immunological synapse (IS) between the CTL and the target cell, which is followed by the secretion of lytic granules from the central part of the IS, the central supramolecular activation complex (cSMAC). Adhesive interactions within the surrounding ring (the peripheral SMAC) maintain contact between both cells and prevent the spread of the contents of the lytic granules to bystander cells. The delivery of lytic granules is mediated by microtubules and depends on the polarization of the centrosome after activation of the CTL (see commentary by Bunnell). Two groups investigated additional mechanisms that regulate the efficiency of CTL-mediated killing. Jenkins et al. performed experiments with CTLs from T cell receptor (TCR) transgenic OT-I mice, which are activated strongly by the ovalbumin peptide SIINFEKL but are weakly stimulated by the modified ovalbumin peptide G4. Microscopy and Western blotting analyses demonstrated that whereas both strong and weak activators of the TCR were sufficient to cause IS formation and centrosome polarization, only strong activators of the TCR triggered polarization of the granules to the cSMAC, which was required for efficient killing. Beal et al. investigated the movements of lytic granules within CTLs on a lipid bilayer system that contained either weak or strong agonists of the TCR. In this system, strong agonists triggered rapid TCR signaling and recruitment of lytic granules to the cSMAC, whereas weak agonists led to a much slower kinetics of granule recruitment, which was associated with inefficient killing. Together, these studies implicate the quality of the TCR signal in contributing to the efficiency of CTL-mediated killing.

M. R. Jenkins, A. Tsun, J. C. Stinchcombe, G. M. Griffiths, The strength of T cell receptor signal controls the polarization of cytotoxic machinery to the immunological synapse. Immunity 31, 621–631 (2009). [PubMed]

A. M. Beal, N. Anikeeva, R. Varma, T. O. Cameron, G. Wasiliver-Shamis, P. J. Norris, M. L. Dustin, Y. Sykulev, Kinetics of early T cell receptor signaling regulate the pathway of lytic granule delivery to the secretory domain. Immunity 31, 632–642 (2009). [PubMed]

S. C. Bunnell, A view to a kill: How ligand quality controls lethal hits. Immunity 31, 531–533 (2009). [PubMed]