Activation of T helper (TH) cells results in the secretion of various cytokines that can determine the fate of an immune response. These cytokines are secreted into areas that are tightly packed with other immune cells, so how do T cells ensure target-cell specificity? Reporting in Nature Immunology, Huse et al. have identified a mechanism by which the specificity of intercellular communication is maintained. They describe two directionally distinct cytokine secretion pathways in TH cells: one towards the immunological synapse — a distinct region formed at the contact zone of the T cell and antigen-presenting cell resulting from the specific reorganization of cell-surface proteins — and another multidirectional pathway.

In this study, Huse et al. show, using intracellular cytokine staining, that the secretion of interleukin-2 (IL-2) and interferon-γ (IFNγ), as well as IL-3 and IL-10, is focused at the immunological synapse in activated TH cells. By contrast, tumour-necrosis factor (TNF) was shown to be focused at the immunological synapse briefly, but as the response developed, TNF became scattered throughout the cell. Using video microscopy, TNF secretion by live TH cells was shown to be distributed throughout the cells, with a bias away from the immunological synapse over time. The intracellular distribution of CC-chemokine ligand 3 (CCL3) and CCL5 was similar to TNF, although with delayed kinetics. In addition, the TH2-cell-associated cytokine IL-4 was found to be distributed throughout the cell.

But how does the cell coordinate the movement of certain cytokines in one direction while sending others on a different route? This study shows that specific trafficking proteins co-localize with certain cytokines at these different locations. RAB3D and RAB19, members of the RAB family of small GTPases — which associate with different intracellular compartments — were found to localize with IL-2 and IFNγ at the synapse, whereas the SNARE (soluble N-ethylmaleimide-sensitive accessory-protein receptor) protein, syntaxin 6, localized with TNF throughout the cell, indicating the use of distinct processes for directional cytokine release.

Together, these results show that T cells differentially direct cytokines, using specific trafficking proteins, through two distinct release pathways. One pathway focuses certain cytokines to the immunological synapse, where localized cell–cell communication can occur, whereas the other pathway releases cytokines, that are mainly associated with inflammation and cell recruitment, into the surrounding milieu in a multidirectional fashion. Therefore, the TH-cell-cytokine response might not depend solely on the type of cytokines induced but also on the method of their release.