ANTAGONISM

T cells are critical immune cells that constantly scan our organism in search for non-self antigens derived from pathogens or tumor cells. Non-self antigen recognition is performed by the T cell receptor (TCR) through a complex signaling cascade that ends up in T cell activation, proliferation and acquisition of effector functions. However, antigens with weak affinity for the TCR that fail to trigger T cell activation are not inert but can dampen the response to non-self antigens, an effect known as antagonism. Such antagonistic effects have been attributed to the existence of a proximal negative feedback mechanism that serves a noise suppression function and enhances T cell antigen discrimination capacities.

Based on these observations, the project proposes to use antagonism as a way to improve our understanding of antigen discrimination. We will investigate where and when antagonism occurs using innovative tools such as patterned substrates and supported lipid bilayers allowing to control and monitor the simultaneous presentation of antigens of different affinities with nanoscale precision, alongside advanced microscopy to visualize T cell responses in real time. The project also delves into the molecular machinery behind antagonism, employing phosphoproteomics and CRISPR-Cas9 gene editing to identify and validate key regulators that may orchestrate the negative feedback loops responsible for this effect. By probing how factors like substrate stiffness, co-stimulatory molecules, and T cell subset diversity (e.g., CD4 vs. CD8, naive vs. memory) influence antagonism, we aim to build a comprehensive model of how T cells integrate competing signals during antigen recognition.

This work will not only shed light on a fundamental aspect of immune regulation but also holds promise for enhancing T cell based immunotherapies.