A Quantitative Multivariate Model of Human Dendritic Cell-T Helper Cell Communication

Cell-cell communication involves a large number of molecular signals that function as words of a complex language whose grammar remains mostly unknown. Here, we describe an integrative approach involving (1) protein-level measurement of multiple communication signals coupled to output responses in receiving cells and (2) mathematical modeling to uncover input-output relationships and interactions between signals. Using human dendritic cell (DC)-T helper (Th) cell communication as a model, we measured 36 DC-derived signals and 17 Th cytokines broadly covering Th diversity in 428 observations. We developed a data-driven, computationally validated model capturing 56 already described and 290 potentially novel mechanisms of Th cell specification. By predicting context-dependent behaviors, we demonstrate a new function for IL-12p70 as an inducer of Th17 in an IL-1 signaling context. This work provides a unique resource to decipher the complex combinatorial rules governing DC-Th cell communication and guide their manipulation for vaccine design and immunotherapies. [Display omitted] •428 protein-level measurements of 36 DC communication molecules and 17 Th cytokines•Data-driven quantitative model of DC-T cell communication extensively validated•Systematic and unbiased predictions of context-dependent mechanisms•Validation of a new context-dependent role of IL-12p70 in Th17 differentiation Grandclaudon et al. show that combinatorial rules that explain communication between dendritic cells and T helper cells can be helpful in vaccine design and immunotherapy.