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Sentinels against microbial invaders

Dendritic cells are sentinels of the innate immune system that activate the adaptive immune system when infectious microorganisms enter the body. Prof. Dr. Klaus Heeg and his team from the Department of Infectiology at the University of Heidelberg are focusing on the complex signalling pathways that link the innate and adaptive immune systems.

Macrophages, B-cells and dendritic cells are referred to as “professional antigen-presenting cells”, i.e. components of the innate immune system that activate specific T-lymphocytes and hence the adaptive (acquired) immune response by presenting antigens (for example of viruses and bacteria) on their surface. These components therefore link the innate and the adaptive immune systems. The dendritic cells are the most important of the three aforementioned cell types in terms of antigen presentation, although their function was discovered much later than the functions of macrophages and B-cells. Nowadays, dendritic cells are at the centre of immunological research.

Dendritic cells

Immunofluorescence image of two dendritic mouse cells with MHC complexes (labelled with red-fluorescent antibodies) on their surface. © University Hospital Heidelberg

The name "dendritic cells" (Greek "dendros" - tree) is derived from the fine cytoplasmic branches protruding from the spherical cells, which gives them a star-shaped morphology. The dendritic cells migrate through the peripheral organs, sampling pathogens such as bacteria and virus-infected cells through a process known as phagocytosis. The foreign antigens are degraded into small peptides and the dendritic cells display these antigens on their surfaces by coupling them to an MHC (major histocompatibility complex) molecule. The dendritic cells then migrate from the site of infection to the lymphatic organs, for example to the closest lymph node, where they present large quantities of processed antigens (MHC-peptide complexes) to the T-lymphocytes. This leads to the activation of antigen-specific T-lymphocytes, which trigger a specific cellular immune response. Antigen presentation is very efficient; an individual dendritic cell is able to activate from hundreds to several thousands of antigen-specific T-cells.

Toll-like receptors

Prof. Dr. Klaus Heeg, Department of Infectiology at the University of Heidelberg © University Hospital Heidelberg

Dendritic cells therefore have a key function in mediating immunity in mammals. They notify the immune system of the presence of infectious microorganisms, they alarm and activate T-lymphocytes, which are part of the adaptive cellular immune response, and induce the death of virus-infected cells or cells that are otherwise dysfunctional or damaged. In addition, dendritic cells can initiate primary immune reactions, including the polarisation of naïve T-cells in specialised sub-populations such as regulatory T-cells (Treg), which suppress the activation of the immune system and preserve the self-tolerance against the body's own antigens, i.e. prevent the development of spontaneous autoimmunity. The differentiation of dendritic cells underlies a very complex regulatory mechanism, which is being investigated by Professor Klaus Heeg and his team at the Department of Infectiology (formerly Hygiene Institute) at the University of Heidelberg. The scientists are specifically focusing on the so-called "Toll-like receptors" (TLRs), receptors that are located on the surface of dendritic cells which enable the immune system to detect intruding microorganisms by recognising so-called "pathogen-associated molecular patterns" (PAMPs). The specific binding of such PAMPs to TLRs induces the activation of the cells. For example, a lipopolysaccharide that is characteristic for Gram-negative bacteria binds to TLR-4, and lipoteichoic acid, which is found in the cell wall of Gram-positive bacteria, binds to TLR-2. TLR-3 specifically binds viral double-strand RNA.

The abbreviation "TLR" and the term "Toll-like receptors" are also used in German. Scientific literature also sometimes uses the terms "signalling pattern recognition receptors" (PRRs). The word "toll" is originally a German, not an English word as might be assumed. TLR got their name from their similarity to the protein coded by the Toll gene identified in Drosophila in the early 1980s at the European Molecular Biology Laboratory in Heidelberg by scientists focusing on the early embryogenesis of Drosophila. The team led by Christiane Nüsslein-Volhard and Eric Wieschaus, who were awarded the Nobel Prize in Physiology or Medicine in 1995 for their groundbreaking discoveries, were very enthusiastic about the characteristics of this gene and its protein, which determines the dorsal-ventral polarity in Drosophila embryos. The name "Toll" derives from Christiane Nüsslein-Volhard's exclamation "Das war ja toll!", which can be translated as "That's fantastic, that's absolutely great". Since then, several mammalian Toll genes, which encode Toll-like receptor (TLR) proteins, have been identified.

TLRs have a highly conserved structure. There are around ten different known human receptors that are homologues of the Drosophila "Toll" protein. IL-1RI, a receptor which binds interleukin 1 (a key cytokine involved in inflammatory reactions), has homologous sequences with "Toll". It is assumed that this protein family consists of components of an old phylogenetic signalling system that plays a key role in morphogenesis, innate immunity and defence reactions against pathogens.

TLRs and SOCS

It has been shown that the stimulation of TLR also induces an opposite effect, namely the expression of feedback inhibitors of cell activation. These inhibitors are mainly intracellular suppressors of cytokine-signalling proteins (SOCS). TLRs and SOCS are expressed by dendritic cell populations in both humans and mice. Prof. Heeg and his team of researchers are focusing on the important role played by these key proteins that link innate and adaptive immunity in a DFG-funded collaborative research centre at the University of Heidelberg (SFB 405, “Immunotolerance and its disorders”; spokespeople: Prof. S. Meuer and Prof. G. Hämmerling).

Schematic representation of the differentiation, maturation and activation of dendritic cells and their stimulation by TLR ligands. © Dept. Infectiology, University Hospital Heidelberg
The SOCS family includes the “cytokine-inducible SH protein” (CIS) and the proteins SOCS1 to 7 that target the “JAK/STAT” signalling pathway. These proteins are members of the so-called “Janus” family of kinases that are associated with the cytoplasmic domains of the cytokine receptor. In an activated state, the Janus kinases phosphorylate other proteins that are referred to as signal transducers and activators of transcription (STAT). The STAT proteins initiate the transcription of genes induced by cytokines. Heeg’s research project focuses on the role of SOCS expression in different differentiation phases and functional states of dendritic cells. A major focus is the influence of SOCS on T-cell activation by mature dendritic cells and hence on the activation of the adaptive immune system.

On the one hand, the Heidelberg researchers use precursor cells derived from mouse bone marrow as “in vitro models”. These precursor cells are stimulated by GM-CSF (granulocyte-macrophage colony-stimulating factor) and differentiate into dendritic cells. On the other hand, the researchers also use human CD14-positive monocytes, a sub-population of white blood cells that are induced by GM-CSF and interleukin 4 (IL-4) to differentiate into dendritic cells.

The researchers are focusing on the systematic analysis of the induced SOCS expression patterns (induced by different factors, including TLR ligands or cytokines) and their effects in the three developmental phases of dendritic cells – differentiation, maturation and activation. In another research project, Heeg and his team have been able to show that TLR activators induce antigen-presenting cells, which in turn induce the differentiation of naïve T-helper cells into regulatory T-cells (Treg).

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