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

• Published in: Cell Vol. 179; no. 2; pp. 432 - 447.e21
• Main Authors: Grandclaudon, Maximilien, Perrot-Dockès, Marie, Trichot, Coline, Karpf, Léa, Abouzid, Omar, Chauvin, Camille, Sirven, Philémon, Abou-Jaoudé, Wassim, Berger, Frédérique, Hupé, Philippe, Thieffry, Denis, Sansonnet, Laure, Chiquet, Julien, Lévy-Leduc, Céline, Soumelis, Vassili
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 03.10.2019; Elsevier
• Subjects: cell-cell communication; dendritic cells; immunology; Life Sciences; mathematical modeling; signal integration; systems immunology; T helper cell differentiation; signal integration; dendritic cells; mathematical modeling; T helper cell differentiation; cell-cell communication; systems immunology; immunology; lineage; differentitation; regulatory network; selection; growth-factor-beta; health; plasticity; stimulation
• ISSN: 0092-8674; 1097-4172
• DOI: 10.1016/j.cell.2019.09.012

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.