Modulation of T follicular helper cells by Rinl

Our immune system protects us against pathogens. It is composed of an innate and an adaptive part. Both together provide an efficient protection against infections. The adaptive immune system relies on two cell types: T cells and B cells. B cells are the source of antibodies which are able to neutralize pathogens by making them innocuous and recognizable to immune cells of the innate immune system. In many cases these B cells need help from T cells to generate these antibodies and also to acquire a memory against the invading microorganism. The T cells involved in this help are called T follicular helper cells (Tfh). B cell responses are the basis for an efficient protection after vaccination. Modulators of B cell responses like Tfh cells are currently in the focus of immunological and medical research, and factors that modulate Tfh cell development and function represent therapeutic strategies to modulate immune responses. Like all cells of an organism Tfh cells communicate with their environment via receptors which detect signals from their surrounding and transmit them towards the inner part of the cell. This induces intracellular processes, and this is how cellular events like cell proliferation and the release of new messenger molecules which can be recognized by other cells are controlled. This is why the regulation and fine tuning of the surface expression of receptors are very important control checkpoints which allow orchestrating the cell-cell communication as well as the communication between cells and their environment. One of these regulatory steps occurs via the so called endocytosis process which causes receptors to be removed from the cell surface and sent to the inner part of the cell. Simultaneously new signaling pathways can be opened inside the cell in this way. A family of proteins which controls endocytic processes is formed by the RIN proteins (RIN1, RIN2, RIN3 and Rin-like). Rin-like (Rinl) was described by us recently and characterized more in detail in a cell culture system. In this study it was shown that Rinl similar to other RIN family members was able to control endocytic processes. We could also show that Rinl was highly expressed in immune specialized organs like thymus and spleen. By generating a Rinl knock-out mouse, we obtained results which point at a role of Rinl in the development of Tfh cells. In our FWF project we propose several biochemical, molecular and cellular approaches to elucidate how Rinl regulates the differentiation of Tfh cells on a mechanistic level. All together we expect to get with our studies medical relevant insights which are based on the generation and regulation of Tfh cells.

Consisting of an innate and an adaptive part, our immune system protects us from danger. The adaptive immune system relies on two cell types: T and B cells. B cells produce antibodies that neutralize harmful organisms such as bacteria or viruses, rendering them innocuous and detectable by immune cells of the innate immune system. B cells receive help from T cells to generate antibodies and to acquire immunological memory against invading microorganisms. T cells that provide this help are called T follicular helper cells (Tfh). B-cell responses are essential for an effective protection after vaccination. Regulation of B-cell responses, as well as responses mediated by Tfh cells, are currently the focus of immunological and medical research. Factors that alter the development and function of Tfh cells also form potential suitable targets for therapeutic strategies leading to 'immune-modulation' - the control of the immune response for therapeutic purposes. Tfh cells communicate with their environment via so-called receptors. These are proteins that are located on the cell surface, perceive signals from the environment and pass them on to the inside of the cell. In this way, cellular processes are controlled. Cellular processes include cell division and proliferation or the release of new messenger substances, which can then be perceived by other cells via receptors. Therefore, the regulation and fine-tuning of the surface expression of receptors is an important checkpoint to control the communication between cells and their environment. One of these regulatory steps occurs through the so-called "endocytosis process", which causes receptors to be removed from the cell surface and sent inside the cell. Thereby new signaling pathways can occur within the cell, leading to new cellular processes and fates. A family of proteins that control endocytic processes is formed by the RIN proteins (Rin1, Rin2, Rin3 and Rin-like). Rin-like (Rinl) was discovered and identified by us. In our study, we were able to show that Rinl regulates endocytosis of a receptor that is important for T cells, the CD28 co-receptor. Altered CD28 endocytosis was associated with changes in the signaling pathways emanating from the CD28 co-receptor, ultimately specifically impacting on the development of Tfh cells. We were able to show that Rinl is an important restrainer of Tfh development, both during immunization, viral infections or aging. Thus, we were able to uncover new mechanisms regulating Tfh differentiation with consequences on human disease like rheumatoid arthritis or lymphoma.