The overall aim of the grant was to determine how the regulatory compartment of the immune system is alerted by infections (aim 1) and how these alterations influence disease susceptibility (aim 2). The project has been very successful and we have published a total of 18 manuscripts with additional ones still under review or in preparation. To analyze the specialization of Tregs during infection and their interaction with effector T cells (aim 1), we have collected and analyzed a comprehensive dataset and were able to identify novel drivers of Treg specialization upon inflammatory challenge as well as novel mediators of specialized and/or selective suppression. With the analysis of the impact of co-inhibitory receptors induced upon infection on the immune response, we have observed that not only the effector immune response is altered but also the tissue damage and repair programs. Infectious challenges thus not only induce the specialization of Tregs with regard to their suppressive function but also enable acquisition of additional, directly tissue protective functions through induced expression of a tissue protective program.
To determine how infection-induced changes can alter disease susceptibility (aim 2), we first investigated the generation of Treg memory. We could clearly show that in the context of the viral infection models used in our studies, no Treg memory is generated. In fact, we observed strong Treg instability upon viral infections and a transient loss of immune regulation. Indeed, we could show that the rapid replenishment of Tregs after viral infection is essential for preventing the development of autoimmune colitis, thus linking a viral trigger to autoimmunity. In our investigation of the impact of infection induced changes on disease susceptibility we have also identified a new type of effector T cells that can be re-activated upon heterologous challenge. We found this memory T cell subset to confer protection upon heterologous infection but to contribute to the development of autoimmunity.
We have thus successfully completed the project and are finishing up some final aspects outside of the grant. Our findings have contributed to advancing our understanding of infection-induced changes on immune regulation and disease susceptibility as intended. In addition, we have uncovered three unexpected findings relating to Treg instability in inflammation, the tissue protective function of Tregs and a rapidly responding subset of effector T cells . This has further extended the scope and the impact of our project.
