Systems analysis of human dendritic cell-T cell communication – DCComm

Communication is central to the function of all living systems, at all organizational scales (from cells to organs and organisms). It is also crucial to the immune system, where there is a need to tightly coordinate actions from different cells and cell types in order to maintain the integrity of an organism. Dendritic cells (DC) are at the forefront of innate immunity, and subsequently stimulate T cells to induce the primary adaptive immune response. In that respect, DC-T cell communication is of paramount importance to immunity against pathogens, and can be perturbed in various situations of immunopathology. DC communicate with T cells through over 60 molecular ligands, sensed by specific receptors on T cells. Past studies have mostly analyzed the communication process by focusing on one or two of these molecules. We were the first to establish a multivariate mathematical model of DC-T cell communication, in which 36 DC communication molecules were integrated, together with their collective impact on CD4 T cell activation and T helper cell differentiation. In this proposal, we aim at the next level in the systems analysis of DC-T cell communication, by introducing novel technologies (35 color flow cytometry, nanostring), increasing the number of DC molecules to be integrated (between 50 and 60), comparing DC-T cell communication of different DC subsets (WP1), systematically analyzing context-dependency (WP2), and introducing antigen specificity (WP3). We hope to uncover novel mechanisms and rules governing DC-T cell communication, with implications in immunopathology, cancer, and vaccine design.