Stromal cells provide networks on which innate and adaptive immune cells interact. Using a combination of primary human samples, mouse models, in vitro culture systems and computational models we have identified key pathways regulating stromal cell function and remodelling during protective immune responses, immune mediated inflammatory disease (IMID) and cancer. Using both human samples and mouse models we have identified a critical role for IL4 receptor signalling pathway in stromal cells in the development of inflammatory stroma in tertiary lymphoid tissue found in Sjogren’s syndrome and characterised its function in pathological stroma in rheumatoid arthritis, Hodgkin’s lymphoma and metastatic tumours. In contrast gamma interferon receptor signalling in human stromal cells drives a highly regulatory stroma characterised by expression of multiple check-point ligands and inhibitory proteins. Similar to innate immune cells, stromal cells express and respond to localised cues including TLR ligands, inducing rapid topological remodelling modulating the timing and efficacy of immune responses to vaccination, a process dependent on miR132. Thus we propose a model where localised stromal cells in tissues sense and respond to environmental cues (cytokines, pathogen products), differentiating into localised effector stroma that shape the type and duration of tissue specific immune responses. By combining computational simulations with experimental models we have been able to use artificial neural networks to identify a novel therapeutic approaches to modulate stroma-immune cell interactions in established IMIDs and verify the computational predictions using a mouse model of Sjogren’s syndrome. This approach of model driven experimentation has the potential to integrate ‘omics’ and biophysical analysis to accelerate identification of potential therapeutic approaches and biomarkers for the treatment of IMIDs, chronic inflammation, infection and cancer.