This study investigates the molecular and cellular mechanisms underlying the systemic response to sepsis, a life-threatening condition caused by infection. By measuring gene expression changes across multiple organs in mouse models of sepsis, the researchers identified a hierarchical cytokine circuit involving tumor necrosis factor (TNF) plus interleukin (IL)-18, interferon gamma (IFN-γ), or IL-1β. These cytokine pairs recapitulated the majority of the host's transcriptional, physiological, and fitness responses to sepsis, suggesting a simplified "pairwise cytokine code" that captures the complex cytokine interactions during sepsis. The study also validated these findings through spatial transcriptomics and cellular perturbation experiments, providing a mechanistic framework for understanding and potentially treating sepsis. Key insights include the rapid resolution of nonlymphoid tissues compared to lymphoid tissues, the hierarchical cytokine interactions, and the impact of these cytokines on specific cell types and tissues, such as hepatocytes, kidney epithelia, colon neurons, splenic B cells, bone marrow erythroid cells, and whole-body neutrophils and macrophages. The work highlights the importance of TNF as a central node in this cytokine module and suggests that targeting specific cytokine pairs could be a therapeutic approach for sepsis.This study investigates the molecular and cellular mechanisms underlying the systemic response to sepsis, a life-threatening condition caused by infection. By measuring gene expression changes across multiple organs in mouse models of sepsis, the researchers identified a hierarchical cytokine circuit involving tumor necrosis factor (TNF) plus interleukin (IL)-18, interferon gamma (IFN-γ), or IL-1β. These cytokine pairs recapitulated the majority of the host's transcriptional, physiological, and fitness responses to sepsis, suggesting a simplified "pairwise cytokine code" that captures the complex cytokine interactions during sepsis. The study also validated these findings through spatial transcriptomics and cellular perturbation experiments, providing a mechanistic framework for understanding and potentially treating sepsis. Key insights include the rapid resolution of nonlymphoid tissues compared to lymphoid tissues, the hierarchical cytokine interactions, and the impact of these cytokines on specific cell types and tissues, such as hepatocytes, kidney epithelia, colon neurons, splenic B cells, bone marrow erythroid cells, and whole-body neutrophils and macrophages. The work highlights the importance of TNF as a central node in this cytokine module and suggests that targeting specific cytokine pairs could be a therapeutic approach for sepsis.