CTLs kill target cells via fusion of lytic granules (LGs) at the immunological synapse (IS). Soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) function as executors of exocytosis. The importance of SNAREs in CTL function is evident in the form of familial hemophagocytic lymphohistiocytosis type 4 that is caused by mutations in Syntaxin11 (Stx11), a Qa-SNARE protein. Here, we investigate the molecular mechanism of Stx11 function in primary human effector CTLs with high temporal and spatial resolution. Downregulation of endogenous Stx11 resulted in a complete inhibition of LG fusion that was paralleled by a reduction in LG dwell time at the IS. Dual color evanescent wave imaging suggested a sequential process, in which first Stx11 is transported to the IS through a subpopulation of recycling endosomes. The resulting Stx11 clusters at the IS then serve as a platform to mediate fusion of arriving LGs. We conclude that Stx11 functions as a t-SNARE for the final fusion of LG at the IS, explaining the severe phenotype of familial hemophagocytic lymphohistiocytosis type 4 on a molecular level. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
CITATION STYLE
Halimani, M., Pattu, V., Marshall, M. R., Chang, H. F., Matti, U., Jung, M., … Rettig, J. (2014). Syntaxin11 serves as a t-SNARE for the fusion of lytic granules in human cytotoxic T lymphocytes. European Journal of Immunology, 44(2), 573–584. https://doi.org/10.1002/eji.201344011
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