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Issue 322: Effective immune-cell responses depend on collective decision-making mediated by diffusible intercellular signaling proteins. Here, we designed a three-dimensional modeling framework to systematically investigate the origin and consequences of spatially inhomogeneous signaling in T cell populations. We found that such inhomogeneities are critical for effective cell-cell signaling, and they do not arise by diffusion and uptake alone, but rather depend on properties of the cell population such as an all-or-none behavior of cytokine secreting cells. Furthermore, we assessed the regulatory properties of negative and positive feedback, and we analyzed tissue architectures such as clustering of secreting cells or vacuum cleaner cells such as regulatory T cells. Overall, our simulations highlight the complex dynamics imposed by cell-cell signaling with diffusible ligands, facilitating fine-tuned biological control especially if combined with feedback mechanisms.