Dissecting the impact of cell interaction strength and stiffness in immune cell communication

Activation of CD4 T cells occurs via antigen-specific cell-cell contacts (immune synapse, IS) and critically depends on plasma membrane as well as nuclear actin dynamics. In addition to MHC-I-T cell receptor (TCR) interactions, integrin-dependent mechanotransduction has been recognized as an important element of signal transmission. However, how variations in adhesion forces at the IS govern individual TCR effector functions remains to be established. To address this, we will apply a synthetic immunology approach to engineer an IS with defined adhesion strength and stiffness in an interdisciplinary team effort. We will design DNA nanostructure linkers and exoskeletons with (i) feature-defined adhesion strength and stiffness, (ii) enable stimuli-responsive and reversible binding and (iii) can be coupled or decoupled from the cytoskeleton to substitute integrin interactions at the IS. The determination of IS adhesion forces and signaling output will provide important new insight into the role of mechanotransduction in TCR-induced actin remodeling and CD4 T cell activation.