Abstract
Cells receive, and adjust to, various stimuli, which function as part of complex microenvironments forming their “context”. The possibility that a given context impacts the response to a given stimulus defines “context-dependency” and it explains large parts of the functional variability of physiopathological and pharmacological stimuli. Currently, there is no framework to analyze and quantify context-dependency over multiple contexts and cellular response outputs. We established an experimental system including a stimulus of interest, applied to an immune cell type in several contexts. We studied the function of OX40 ligand (OX40L) on T helper (Th) cell differentiation, in 4 molecular (Th0, Th1, Th2, and Th17) and 11 dendritic cell (DC) contexts (monocyte-derived DC and cDC2 conditions). We measured 17 Th output cytokines in 302 observations, and developed a statistical modeling strategy to quantify OX40L context-dependency. This revealed highly variable context-dependency, depending on the output cytokine and context type itself. Among molecular contexts, Th2 was the most influential on OX40L function. Among DC contexts, the DC type rather than the activating stimuli was dominant in controlling OX40L context-dependency. This work mathematically formalizes the complex determinants of OX40L functionality, and provides a unique framework to decipher and quantify the context-dependent variability of any biomolecule or drug function.
Highlights
Context-dependency is a well-known biological phenomenon acknowledged by scientists since decades
T helper (Th)-polarizing contexts We started by studying the function of OX40 ligand (OX40L) in four prototypical Th-polarizing cytokine contexts: Th0, Th1 (IL-12), Th2 (IL-4), and Th17 (IL1β + IL-6 + IL-23 + TGF-β)
A major challenge in studying context-dependency lies in the tremendous diversity of possible contexts, which can be viewed at several levels: individuals, organs, sub-anatomical locations, or microenvironmental niches
Summary
Context-dependency is a well-known biological phenomenon acknowledged by scientists since decades It has been observed and described in a variety of physiological and pharmacological situations. We know that contextdependency may induce tremendous variability in the function of any cellular stimulus, biomolecule, or drug[1,2] It explains a large part of the unpredictable tissue-, organ-, individual-, and disease-related variability in response to stimulus[3,4]. The biological context is the environment in which cells and multicellular systems function It is the result of a multiplicity of components that are interconnected and tightly regulated. This regulation occurs at several levels and allows cells to adjust to the situation and communicate via output signals. A specific signal hitting a cell in a given context leads to an output response, but when the context composition changes, the integration of this specific signal is affected and the resulting cellular output can be qualitatively and quantitatively modulated
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