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Humboldt-Universitaet zu Berlin - Collaborative Research Center for Theoretical Biology

Integration of signal transduction and cytokine expression in T helper lymphocytes

Memory for pathogens is a hallmark of adaptive immunity. Long-term protection against reinfections is provided by memory T and B lymphocytes. In the previous funding period, we have combined mathematical modelling and in-vitro experiments to elucidate dynamic molecular networks that govern the proliferation of T lymphocytes, the differentiation of T helper type-1 (Th1) memory cells, and the expression of T-cell cytokine genes. To understand the stability and adaptability of immunologic memory, we have modelled the competition of memory cells for survival niches and shown under which conditions long-lived plasma cells in the bone marrow can support stable humoral memory.

Based on these results we will study the generation and differentiation of T-cell memory in vivo, complemented by further in-vitro experiments. At the level of intracellular regulation, we will dissect the transcriptional network that governs the differentiation and stability of Th17 cells, expressing IL-17 and being involved in chronic inflammation and autoimmunity. While the components of this network are largely known, how their interactions shape stable memory for IL-17 expression is not clear. By iteratively quantifying the kinetics of the network components, modelling the network dynamics, and applying network perturbations using knockout mice and siRNA/shRNA, we will develop an integrated and predictive model for the generation of Th17 memory.

Extending our approach to the population dynamics of T cells, we will study how molecular and cellular interactions control the generation and long-term maintenance of the memory T cell pool reactive to a specific pathogen. To rationalise the complex data sets on differentiation of memory cells from effector cells, survival in specific (bone-marrow) niches, and activation upon reencounter with cognate antigen, we will develop models of T-cell memory at the level of cellpopulation dynamics. We will study how the longevity and adaptability of memory is shaped by interclonal and/or intraclonal competition for limited survival niches. These investigations will lead to a more profound understanding of T-cell differentiation dynamics and may contribute to the design of efficient strategies for cell-based immunotherapies.

description of the 1st period german version
description of the 2nd period