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Analysis of lymphocyte survival and pathogen persistence

A proper functioning immune system is essential for life. In case of a dysfunctional immune system, we would be highly vulnerable towards a range of infectious microbes. In addition, the immune system is important for the detection and destruction of tumor cells that are recognized as abnormal. On the other hand, immunity nees to be highly regulated since an overreactive or dysregulated immune system will cause autoimmunity, thereby attacking and destroying self-tissue.

Our laboratory is investigating how immune cells integrate input signals from the environment to initiate responses towards different stimuli. Such stimuli can originate from invading microbes, potentially causing infections, or, alternatively, from self-tissue causing autoimmunity.

We are thereby focusing on macrophages, cells that are the prime scavengers of infectious material, and T cells, that can execute an immune response against antigens in a highly specific manner. We are particularly interested in the mechanisms that underlie homeostasis of peripheral T cells, a process that is not well understood. We are also investigating how certain pathogens can trick the immune system to escape immune detection.

We are employing a spectrum of techniques, including basic biochemistry, molecular biology, proteomics, flow cytometry, microscopy, including live cell imaging, as well as mouse genetics. Using these technologies, we aim to gain a better understanding of the mechanisms involved in immune cell activation and T cell homeostasis.

Interaction of M. tuberculosis with host macrophages

One model system that we are studying is the interaction of M. tuberculosis with host cells. M. tuberculosis is arguably one of the most successful pathogens on earth, having evolved a plethora of strategies to subvert host immunity. One reason for the extreme virulence of M. tuberculosis is their exquisite capacity to withstand the microbicidal environment of the macrophage. Our laboratory has contributed to the elucidation of a number of such strategies, that include the utilization of both bacterial-derived factors as well as host-derived molecules for the protection of M. tuberculosis within macrophages. An example of a bacterium-derived survival factor is the mycobacterial serine/threonine protein kinase G (PknG). How, exactly, PknG mediates the intracellular survival of M. tuberculosis remains unclear and we are currently establishing systems to analyze its molecular function during an infection in macrophages.

Our work also led to the identification of coronin 1, a member of the highly conserved coronin protein Family, as a host factor involved in mycobacterial survival. Using in vitro and in vivo model systems, we have shown a role for coronin 1 in the odulation of the Ca2+/calcineurin pathway, thereby preventing the destruction of mycobacteria within macrophages. Also, we have showed that upon inflammatory stimuli, coronin 1 activates phosphoinositol (PI)-3-kinase in order to induce the rapid elimination of pathogens.

Regulation of naïve T cell homeostasis by coronin 1

By studying a mouse model in which we depleted coronin 1, we found that coronin 1 is essential for the survival of peripheral naïve T cells while being dispensable for T cell development and selection. As a consequence, in both mice and men, mutations in coronin 1 are associated with a profound depletion of naïve T cells in peripheral lymphoid organs (see Figure 1). Interestingly, the absence of coronin 1 results in resistance towards a variety of autoimmune stimuli as well as a tolerance towards donor organs following transplantation. Despite the absence of auto- and alloimmunity upon coronin 1 deletion, coronin 1-deficient T cells continue to fight infections. We found that coronin 1 modulates a signaling pathway that produces the second messenger molecule cAMP. In the absence of coronin 1, cAMP levels drastically increase in T cells, thereby making these cells tolerogenic to the transplanted organ. However, when challenged with microbial infections, microbes induce the expression of co-stimulatory molecules on antigen presenting cells that neutralize the cAMP-mediated suppression, allowing appropriate control of infections. Ongoing studies are aimed at further dissecting the coronin 1-dependent signaling pathway as well as understanding the role for coronin 1 in the regulation of naïve T cell homeostasis.

A conserved pathway sensing cell surface stimulation?

Coronin 1 is one of seven coronin molecules expressed in mammalian cells; whether or not there is redundancy among the different coronins remains unknown. We have initiated a project in which we analyze the role of the coronin 1 homologue in the lower eukaryote Dictyostelium discoideum, that expresses only a single short coronin isoform. It turns out that in Dictyostelium, coronin is required for the initiation of the developmental processes such as multicellular aggregation upon starvation, that involves activation of the cAMP/protein kinase A pathway. Current work aims to unravel the molecular details of the coronin-mediated activation of the cAMP/PKA pathway leading to Dictyostelium multicellular development. We are also investigating new genetic players and molecular pathways involved in Dictyostelium multicellular development.

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