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Modeling how cytokine communications regulate the phenotypic variability of immune cells across spatio-temporal scales

Gr茅goire Altan-Bonnet

National Cancer Institute, NIH

Cytokine-mediated communications are critical for leukocytes of the immune system to integrate their individual responses into tissue-level and context-appropriate responses. The distance and the timing over which this communication happens in immune tissues and tumors must be highly variable (to match varied pathogenic onslaughts) yet tightly regulated (to avoid autoimmune mistakes).

We will present recent theoretical and experimental results demonstrating how a simple diffusion-consumption mechanism quantitatively describes the spatial spread of cytokines; this mechanism explains how localized niches of high cytokine concentrations self-assemble in dense tissues. The volumes of these cytokines niches are determined by the competition between cytokine diffusion and absorption by cells surrounding the cytokine source. In turn, the variability of niche sizes accounts for the cell-to-cell heterogeneity of cytokine responses that is so critical to the plasticity of immune responses.

We will also hash out how individual cells enforce tissue-level memory of inflammation by coordinating their response across long timescales. We uncover a new mode of time integration, whereby cancer and immune cells rely on their surface phosphatidylserine to mediate the catch & release of inflammatory cytokines. This mode of cytokine communications converts transient exposure to cytokines into long-term inflammation.

To conclude, we will discuss how quantitative approaches bring a mechanistic understanding to address fundamental issues in immunology and to design better immunotherapies.