Periodic Reporting for period 4 - Immune Regulation (How Infection History Shapes the Immune System: Pathogen-induced Changes in Regulatory T Cells)
Période du rapport: 2020-12-01 au 2022-05-31
Studying host-pathogen interactions by focusing on the interaction of a single pathogen with the host has defined our understanding of these events and the insights gained form the basis for the therapeutic and vaccination strategies we use today. However, people become infected with multiple pathogens throughout their lifetime, at times even simultaneously. Still, it is largely unknown how the immune response to one pathogen alters the body’s ability to respond to a second infectious agent or the susceptibility to autoimmunity or cancer. This project addresses this question by focusing on infection-induced changes in regulatory T cells (Tregs) as they may lead to biased suppression and changes in the nature of subsequent immune responses. Our efforts focused on two aspects: on one hand, we investigated how infections shape the Treg compartment. We defined the transcriptional program and the Treg specific markers of specialized Treg subsets generated during upon infection and identified the mechanisms they use to interact with effector T cells. Furthermore, we observed the induction of a tissue protective program in Tregs following infections. On the other hand, we investigated how infection-induced changes in T cells affect disease susceptibility. In this context, we found changes in the Treg compartment to be transient but these transient alterations can have a long-term impact on the initiation and accumulation of autoimmune responses. Furthermore, we identified a T cell subset that persists after pathogen encounter that acts in a protective manner upon infectious challenge but can promote the onset of autoimmune disorders. Collectively the experiments performed within this project addressed how preceding infections affect disease susceptibility and how these processes may be modulated. Deciphering how infection history shapes the Treg compartment and how this affects susceptibility to future challenges will lay the groundwork for addressing this question more broadly in the future and as such may have a transformative impact on the field.
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.
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.
We have analyzed the regulatory T cells arising in the context of a polarized infection to an unprecedented depth and have found evidence for thus far unknown specific suppressive mediators employed by regulatory T cells.
Our analysis of Treg memory and the long-term pathogen-induced changes in the regulatory compartment has revealed new perspectives and potential functional roles for regulatory T cells that could have far-reaching implication for a wide range of diseases, including chronic infections, transplantations and autoimmunity.
Our analysis of Treg memory and the long-term pathogen-induced changes in the regulatory compartment has revealed new perspectives and potential functional roles for regulatory T cells that could have far-reaching implication for a wide range of diseases, including chronic infections, transplantations and autoimmunity.