Inter-Organelle Tethering to Lysosome Determines Directional Cytokine Transport in CD4 + T Cells

Delivery of vesicles to their desired destination plays a central role in maintaining proper cell functionality. In certain scenarios, depending on loaded cargos, the vesicles have spatially distinct destination. For example, in T cells, some cytokines (e.g. IL-2) are polarized to the T cell-target cell interface, whereas the other cytokines are delivered multi-directionally (e.g. TNFα). Here we show that in CD4+ T cells, both TNFα+ and IL-2+ vesicles can tether with lysosomes by forming membrane contact sites. Tethered cytokine-containing vesicle (CytV)-lysosome pairs are released sequentially. Only lysosome-tethered CytVs are preferentially transported to their desired destination. Lysosome-tethering regulates the direction of cytokine transport by selectively attaching different motor proteins, kinesin and dynein, to the corresponding CytVs. These findings establish the previously unknown inter-organelle tethering to lysosomes as a universal solution for directional cytokine transport in CD4+ T cells. Modulating tethering to lysosomes can, therefore, coordinately control directionally distinct cytokine transport.