Prof. Dr. Christian Kurts
Tel +49 228 287 - 11050
Fax +49 228 287 - 11052
Our main interests are the mechanisms governing antigen-presentation and the ensuing immune-response in the defense against infections and in immune-mediated diseases. We focus at 3 major topics:
T lymphocytes (=T cells) defend our body against infections with microbes. They require activation by antigen-presenting cells, in particular dendritic cells (DCs). These DCs collect antigens in various tissues, migrate to draining lymph nodes, and activate the T cells there. The mechanism of cross-presentation enables DCs to activate CD8+ T cells (Kurts et al, Nat Rev Immunol, 2010), which are crucial for the immune defense against viruses, intracellular bacteriae and tumors, and in vaccination (Figure 1).
We have previously shown that DCs can also destroy harmful CD8+ T cells, and thereby prevent them from damaging our own body. This form of peripheral immune tolerance is known as cross-tolerance. If it fails, autoimmune diseases result, such as type I diabetes mellitus or multiple sclerosis (Figure 2). Other forms of peripheral immune tolerance include the induction of regulatory T cells, which can suppress harmful T cells. We are interested in suppression of harmful B cells, and prevention of autoantibody formation, which play important roles in various autoimmune diseases such as glomerulonephritis or rheumatoid arthritis (Figure 2).
Our third topic of interest is the role of dendritic cells and other myeloid cells in local immune responses regulation non-lymphoid tissues, with a special emphasis on the urogenital tract (Kurts et al, Nat Rev Immunol, 2013). We wish to understand the immune mechanisms underlying diseases such as glomerulonephritis, and cystitis/pyelonephritis: Furthermore, we study DCs in the eye, the intestine and the heart.
The cell biology of cross presentation is one of the greatest enigmata in this field. For a long time, it was thought that antigen “crosses” from late endosomes into the MHC class I presentation pathway. We have shown that antigen needs to be taken up by distinct receptors, such as the mannose receptor, into a indistinct endosomal compartment for cross-presentation (Burgdorf et al, Science 2007). Loading of MHC I molecules with antigenic peptides occurs in this compartment, and this process is regulated by TLR/MyD88-signaling, which translocated the molecular machinery from the endoplasmic reticulum to the endosomes (Burgdorf et al, Nat Immunol, 2008). These findings showed that TLR signaling not only controls signal 2 of T-cell activation (costimulation), but also signal 1 (Antigen presentation). Furthermore, we identified the elusive organelle for cross presentation of soluble antigen.
Cross presentation requires direct interaction of several immune cells, i.e specific CD8+ and CD4+ Th cells, CTL). CD4+ Th cells need to provide a second opinion as to whether an antigen presented by the DC warrants CD8+ T cell activation (= classical cross priming). We have shown that also NKT cells can provide this second opinion (= alternative cross priming). Furthermore, while Th cells induced production of CCR5-binding chemokines, NKT cells caused DCs to produce CCR4-binding chemokines. Both chemokines synergistically enhance the efficiency of cross presentation (Semmling et al, Nat Immunol, 2010). Based on our findings, it has been proposed to term these chemokines „Signal 0“, in extension of the classical “Signal 1&2” hypothesis by Bretscher und Cohn. Signal 0 chemokines allow CD8+ T cells to more efficiently locate those DCs that present relevant antigen. We currently study the underlying mechanisms and whether other chemokine receptors are involved in immune cell migration during cross-priming.
Regulatory T cells (Treg) are well known to control autoreactive T cells. Less is known about their role in regulating harmful B cells. We have shown in vivo that Tregs prevent the production of auto-antibodies against self antigens in the pancreas or the kidney by inducing B cell apoptosis. To this end, Tregs express PDL-1 and physically interact with the PD-1+ B cells (Gotot et al, PNAS 2012). These findings showed that Tregs directly suppress the rather than indirectly by curbing help through follicular helper T cell. Normally, PD-1 signaling in these cells stimulates B-cell responses through CD40 signaling. However, in the case of autoantigens, Tregs are present and their suppressive effect on B prevails. These findings also explained why PD1 deficiency in mice and men led to autoantibody formation. We are currently employing these findings for the treatment of autoantibody-mediated diseases.
4. DCs and macrophages in urinary tract infection
We have generated novel tools to study kidney diseases and DCs (Tittel et al, Nat Methods 2012). We showed that kidney DCs are the first cells that sense invading bacteria in pyelonephritis and respond by producing chemokines and cytokines, which recruit immune effector cells for rapid innate immune defense (Tittel et al, JASN 2011).
In the bladder we identified a novel immune regulatory function of certain macrophages that use the cytokine TNF to regulate the immune response of neutrophilic granulocytes in bacterial infection (Schiwon et al, Cell, 2014).
5. Dendritic cells in kidney disease
We were among the first to describe DCs in the kidney (Krüger et al, JASN 2004). We demonstrated that DCs promote glomerulonephritis progression by presenting glomerular antigen to Th cells (Heymann et al, J Clin Invest 2009; Hochheiser et al, JASN 2011). These findings clarified why tubulointerstitial infiltrates are tightly associated with nephritis progression, and identified kidney DCs as a therapeutic target.
Our recent work identified the fractalkine receptor CX3CR1, a widely used marker for mononuclear phagocytes with unknown function, as kidney-specific chemokine receptor (Hochheiser et al, J Clin Invest, 2013). These findings identified a selective therapeutic target in glomerulonephritis.
Finally, we study the role of inflammasomes in kidney fibrosis, the common end-stage of many kidney diseases that leads to irreversible loss of kidney function and the need to undergo dialysis.
We discovered that post-operative ileus (POI) is an immune-mediated disease induced by pathological interaction between intestinal muscle cells and immune cells. POI is the most prevalent complication after intestinal surgery and results in serious medical complications and billions of cost to the health system. We discovered that intestinal DCs sense the surgical trauma and stimulate resident Th1 memory cells. These recirculate through the body and settle in all gut segments. There, they produce IFNg that stimulates resident macrophages to produce nitric oxide, which directly paralyses intestinal muscle cells, causing ileus (Engel et al, Nat Medicine 2010).