LAT-independent triggering of granule-mediated cytotoxicity of CD8 T cells (109.32)

Abstract

Abstract LAT (Linker for activation of T cells) is a transmembrane adaptor protein that is integral to the TCR-mediated signaling. LAT has been shown to play an essential role in thymocyte development, T cell activation, and cytokine production by CD4 T cells. Conventional thinking assumed that LAT is also required for the effector function of CD8 T cell. In this study, we used LAT conditional knockout mice to study the function of LAT in the cytotoxicity of CD8 T cells. Surprisingly, although CTL cytotoxicity is reduced in the absence of LAT, it is not completely abrogated. This cytotoxicity appears to be mediated through a granule-dependent, Fas-independent pathway. We further dissected the effect of the LAT deletion within each step of granule exocytosis. LAT-deficiency led to the formation of unstable synapses, subsequently causing unstable T:APC conjugates. Moreover, MTOC polarization and granule reorientation were impaired by LAT-deficiency. Further investigation revealed that, even though TCR-mediated signaling was severely impaired, the residual calcium flux and PLC activity in LAT-deficient CTLs were sufficient to support cytotoxicity. Our study reveals a novel finding that, in contrast to helper T cells, CTL function is not entirely dependent on LAT and, perhaps is not governed by the overall TCR signaling strength.