SFB854 - B31N Dynamic imaging and modelling of the regulation of T cell - pathogen equilibration during chronic infection

The mechanisms which, during chronic infections, permit the equilibration of the immune response with pathogen burden have remained enigmatic. In particular, it is unknown how the interactions of effector and regulatory T cells (T_eff and T_reg) among each other, and with the pathogen, might impact the establishment of a persisting pathogen reservoir. We have recently developed a genetically encoded reporter system for analyzing in vivo the viability of the intracellular pathogen Leishmania major (L. major). This system will enable us to map pathogen viability concomitantly with immune cell recruitment and activation during the establishment of a chronic infection.
Quantitative data from these experiments will be used to develop and validate differential equation-based models for equilibration of pathogen burden versus the T_eff response over the course of the infection. Data-driven model selection will allow dissecting by which mode of action the T cell-mediated activation of phagocytes controls the parasite throughout the course of the infection (i.e. direct pathogen killing versus growth inhibition, phagocyte-intrinsic versus tissue-wide control). Furthermore, we will analyze the molecular signaling dynamics underlying T_eff and T_reg function delivery at the site of infection. For this, we will investigate by intravital 2PM the behavior of T cells expressing fluorescent in vivo reporters for proximal TCR signaling. These data will be used to inform a spatio-temporal agent-based model of immune-pathogen interactions. The mathematical model will allow testing in silico different hypotheses of how the interactions between T_eff, T_reg and antigen-presenting cells (APCs) impact on the activation of the T cells during the establishment and maintenance of chronic infection. These hypotheses will be validated in vivo by manipulating cytokine signaling, antigen presentation and immunological checkpoints during intravital 2-photon microscopy (2PM). Taken together, the presented project will elucidate (1) the modes of pathogen containment into which T cell effector functions are translated during the establishment of chronic infections, and (2) the dynamics of T cell activation signaling underlying the interactions of T_eff, T_reg and APCs in this process. These results will reveal, on the one hand, T cell strategies in the fight against invading pathogens and, on the other hand, pathogen strategies for immune evasion. Both might define novel intervention points for antimicrobial as well as immunomodulatory therapeutic approaches.