Quantitative modeling of the collective tuning of T cell activation.

Sloan-Kettering Inst Can Research, New York NY

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Abstract

? DESCRIPTION (provided by applicant): Our project is an experimentally driven modeling effort to probe the dynamics of cell-cell communications in the adaptive immune system. T lymphocytes rely on cytokine communications to translate individual cell activation into collectively synchronized responses at the population level. In that context, regulatory T (Treg) cells are critical components of the immune response that can arbitrate every aspect of T cell activation (from antigen signaling to differentiation), through competition with effector T (Teff) cells for soluble cytokines. We conjecture that the buffering of cell-cell communication cytokines within mixed populations of Teff cells and Treg cells creates a dynamic hurdle that Teff cells must overcome to validate and pursue their own activation. We will test this conjecture by: Modeling how cooperation and competition through the IL-2 pathway synergizes with the antigen response and shapes the repertoire of responding Teff cells. Testing how time integration of IL-2/IL-7 signals mediates cell fate decision between proliferation and homeostasis. * Modeling the adaptive role of Treg cells in shaping CD4+ Teff cell differentiation. For each of these specific aims, we will use an integrated approach with: quantitative in vitro and in vivo characterization of T lymphocyte activation at the single-cell level and at the population level. computational modeling of cell-cell communications with explicit and accurate biochemistry (to encompass our quantitative experimental data and to uncover new regulations). testing our quantitative models of cell-cell communications in the immune system by designing, optimizing and validating targeted cytokine manipulations towards clinical applications. RELEVANCE Perturbations of lymphocyte-lymphocyte communications through cytokine injection and blocking are promising avenues for clinical immunotherapies. However, cytokine regulations are so complex that it warrants the development of quantitative models to tease out their overlapping positive and negative effects on T cell activation. The key of our approach is the tight integration of experimental measurements and model development to deliver a biochemically accurate model of the integration of signal transduction, gene regulation and proliferation/death in T lymphocytes. We will use this quantitative methodology to design and test new protocols of immunotherapeutic manipulations.