Institute of Molecular Medicine
Group Dr. Andreas Limmer

1. Research overview
2. Research topics
3. Group members
4. Grant support
5. Principal investigator
6. Publications

Research overview

Antigen-specific T cell responses as part of the adaptive immunity are needed to clear infections or fight tumors. To prevent destruction of healthy uninfected tissue, T cell activation is tightly regulated. Therefore, only professional antigen presenting cells (APC) in secondary lymphatic tissues (e.g. lymph node or spleen) are capable to activate T cells. In addition, before APCs such as dendritic cells (DC) can activate T cells, they have to be activated themselves. This so called “licensing” of DCs occures via pathogenic structures/patterns, which bind to extra- and intracellular pattern recognition receptors (PRR), such as Toll-like receptors, NODs or helicases (MDA5, RIG-I etc.).

While most people look at infections and PRR-ligands as stimulators of innate and adaptive immunity, we are mainly interested to find out, why and how adaptive T cell responses are suppressed or counter-regulated. It becomes increasingly known that it is equally important to shut down immune responses as it is important to trigger them.

Besides trying to understand how immune responses are controlled in general, my group concentrates on CD8 T cell immunity. Even more restrictive, we additionally focus on CD8 T cell responses against systemic infections and self-proteins in the spleen. 

While lymph nodes are specialized to collect and present tissue-derived antigens to T cells, the spleen filters antigens from blood and induces immunity or tolerance. Induction of immunity depends on various factors leading to the licensing of DCs by pathogen associated molecular patterns (PAMP) or by CD4 help. Tolerance induction is not just a lack of stimulation, but is a complex process itself, including the induction of regulatory/tolerogenic DCs by suppressive cytokines and the selective induction of regulatory T cells.
Overall those mechanisms regulating tolerance and immunity have to guarantee that autoimmunity is prevented while immunity against infections is induced.
A major difference to LN is that in the spleen antigens (pathogen and selfantigens), DCs and T cell enter the spleen via the same route, i.e. arterial blood, while in the LN antigens are transported into the T cell zone via activated (licensed) DC and T cell enter the T cell zone via high endothelial venules (HEV).  Because of these differences special regulatory mechanisms are necessary in the spleen to differentiate between self-antigens and pathogens.

 

Research topics

Immune regulation in the spleen

We have recently described, that TLR-L such as CpG, induce immunity when injected subcutaneously but suppress T cell responses when applied systemically (Wingender et al. 2006). This suppression was dose-, time and location dependent. Furthermore, we could show that CpG-DNA induced the expression of IDO in the spleen, but not in lymph nodes and that IDO was responsible for the lack of T cell function observed in vitro and in vivo. Until now we could further show that the suppressive mechanism induced by CpG in spleen was not restricted to IDO, but rather seems to involve a broad spectrum of mechanisms, such as cytokine suppression (IL-12, TNF, IL-6), deletion and reorganization of the splenic structure.

As we have observed that various immune responses against infections (such as adenovirus, listeria) are strictly dependent on the spleen, we want to find out how immune responses in the spleen are regulated.

Project 1)

In a close collaboration with Joke den Haan and Georg Kraal from Free University Amsterdam, we have found out that metallophillic marginal zone macrophages (MMM), which build a barrier between the marginal zone and the T cell zone, can take up and transfer antigen to CD8+DC for cross-presentation to CD8 T cells. To understand the transfer process, we will continue to investigate the role of gap junctions and exosomes, two mechanisms already known in the literature to be responsible for antigen transfer.

Project 2)

Based upon our initial findings that bacteria and PAMPS can suppress adaptive immune responses, we are currently investigating how in sepsis bacteria are recognized and which mechanisms are responsible for the induction of immune paralysis, i.e. suppression of adaptive immune responses against secondary infections (adenovirus, Listeria and influenza (H1N1)).

Project 3)

While we have initially shown that systemic CpG-DNA and LPS can suppress adaptive T cell responses, various other TLR-L have meanwhile shown to be suppressive, if given systemically and before a bacterial or viral infection.
Here we investigate the role of type I IFN inducing substances and infections on the induction of CD8 T cell immunity. We are especially interested to identify the cell-type inducing type I IFN and thereby influencing the induction of CTL activity. As it has turned out, not only the place, but also the timing when DC and T cells have contact to type I IFN determines whether CTL activity is induced or suppressed (loco-temporary immune regulation).

Tumor immunology

Most patients do not die from the primary tumor but rather succumb to uncontrolled metastases. As early diagnosis of metastases is essential for the induction of a successful therapy and survival, better diagnostic tools are required.

In a coordinated BMBF project, we are currently developing “nano-detectors”, which shall be used to “fish” rare circulating tumor cells in the blood of tumor patients. By fishing in the whole body (up to 30L due to blood circulation) instead of in a small volume (ca.10ml), chances to identify circulating tumor cells should increase by many folds. The surface of the nano-detector is coated with antibodies specific for tumor surface molecules known to be expressed on metastasizing tumor cells, e.g.  EpCAM. It is intended to fish tumor cells and identify them by establishes methods, such as RT-PCR and histology.

Group Members

Patricia Schmidbauer, Research Technician

Timo Schwandt. PhD student

 

Grant support

SFB 704

KFO115

BMBF (winner of “Innovationswettbewerb Medizintechnik 2007”)

 

Principal Investigator

Personal data

Name: Dr. Andreas Limmer (PhD)

Work address:   Institute for Molecular Medicine and Experimental Immunology
                        Uniklinikum Bonn/ Haus 10
                        Sigmund-Freud-Str. 25
                        53105 Bonn/ Germany
                        Tel.: +49 228 287 11040
                        Fax: +49 228 287 11343
                        E-mail: andreas.limmer@ukb.uni-bonn.de

Education

1986-1993:    Study of Biology at the University of Regensburg

1990-1991:    Exchange student at the Washington University, St. Louis, USA in the lab of Prof. Dr. Dennis Y. Loh MD
                     Topic: ”Role of CD8-bound lck for CD8 T cell activation and tolerance induction in the thymus”

1992-1993:    Diploma work at the German Cancer Research Center in the labs of Prof. Dr. G. Hämmerling/ Prof. Dr. B.Arnold.
                     Topic: ”Activation of anergic T cells in vivo”

1994-1997:    Graduate studies at the German Cancer Research Center (DKFZ) in the labs of Prof. Dr. G. Hämmerling/ Prof. Dr. B.Arnold.
                     Topic: “From autoimmunity to autoaggression. Studies in a transgenic mouse model.”

1998-2002:    Postdoctoral fellow in the lab of. Dr. med. Percy. Knolle at the Center for Molecular Biology Heidelberg (ZMBH) at the university of Heidelberg.
                     Topic: “Local immunregulation in the liver- the role of liver sinusoidal endothelial cells (LSEC) for systemic T cell tolerance.”

2003-           Group leader at the „Institute for Molecular Medicine and Experimental Immunology“ (IMMEI).
                    Focus: “Influence of systemic infections and TLR-ligands on the balance between immunity and tolerance in the spleen.”

 

Publications

Backer R, Schwandt T., Juengerkes F., Greuter M, Oosting M, Tuting T, Boon L, O’Toole T, Kraal G, Limmer A* & den Haan JMM*. Effective collaboration between marginal metallophilic macrophages and CD8+ dendritic cells in the generation of cytotoxic T cells. PNAS 2009 in press. (* contributed equally)

Kern M, Popov A, Scholz K, Schumak B, Djandji D, Limmer A, Eggle D, Sacher T,  Zawatzky R, Holtappels R, Reddehase MJ, Hartmann G, Debey-Pascher S, Diehl L, Kalinke U, Koszinowski U, Schultze J, Knolle PA. Virally Infected Mouse Liver Endothelial Cells Trigger CD8(+) T-Cell Immunity. Gastroenterology 2009. [Epub ahead of print]

Klotz L, Hucke S, Thimm D, Classen S, Gaarz A, Schultze J, Edenhofer F, Kurts  C, Klockgether T, Limmer A, Knolle P, Burgdorf S. Increased antigen cross-presentation but impaired cross-priming after activation of peroxisome proliferator-activated receptor gamma is mediated by up-regulation of B7H1. J Immunol. 2009 Jul 1;183(1):129-36.  

Ney JT, Schmidt T, Kurts C, Zhou Q, Eckert D, Felsher DW, Schorle H, Knolle P, Tüting T, Barchet W, Büttner R, Limmer A, Gütgemann I. Autochthonous liver tumors induce systemic T cell tolerance associated with T cell receptor down-modulation. Hepatology. 2009 Feb;49(2):471-81. Erratum in: Hepatology. 2009.  

Engel DR, Maurer J, Tittel AP, Weisheit C, Cavlar T, Schumak B, Limmer A, van  Rooijen N, Trautwein C, Tacke F, Kurts C. CCR2 mediates homeostatic and inflammatory release of Gr1(high) monocytes from the bone marrow, but is dispensable for bladder infiltration in bacterial urinary tract infection. J Immunol. 2008.  

Busch A, Quast T, Keller S, Kolanus W, Knolle P, Altevogt P, Limmer A. Transfer of T cell surface molecules to dendritic cells upon CD4+ T cell priming  involves two distinct mechanisms. J Immunol. 2008 Sep 15;181(6):3965-73.  

Kornek M, Lukacs-Kornek V, Limmer A, Raskopf E, Becker U, Klöckner M, Sauerbruch T, Schmitz V. 1,2-dioleoyl-3-trimethylammonium-propane (DOTAP)-formulated, immune-stimulatory vascular endothelial growth factor a small interfering RNA (siRNA) increases antitumoral efficacy in murine orthotopic hepatocellular carcinoma with liver fibrosis. Mol Med. 2008 Jul-Aug;14(7-8):365-73..  

Schildberg FA, Hegenbarth SI, Schumak B, Scholz K, Limmer A, Knolle PA. Liver  sinusoidal endothelial cells veto CD8 T cell activation by antigen-presenting dendritic cells. Eur J Immunol. 2008 Apr;38(4):957-67. Erratum in: Eur J Immunol. 2008 Jun;38(6):1767. Scholz, Kai [added].

Berg M, Wingender G, Garbi N, Djandji D, Hegenbarth S, Momburg F, Hämmerling GJ, Limmer A* and Knolle PA*: Cross-presentation of apoptotic tumor cells by liver sinusoidal endothelial cells induces tumor-specific T cell tolerance and presents tumor eradication. EJI 2006:36:2960. (* contributed equally)

Wingender G, Schumak B, Jüngerkes F, Garbi N, Busch A, Berg T, von Bubnoff D, Steitz J, Lenz J, Schüler T, Moldenhauer G, Takikawa O, Asselin-Paturel C, Busch D, Heit A, Huster K, Busch D, Kalff J, Schwarz N, Kurts C, Endl E, Trinchieri G, Tüting T, Wagner H, Hämmerling GJ, Knolle PA and LimmerA: Systemic rather than local application of CpG-DNA suppresses adaptive immunity via induction of IDO and suppression of IL-12 production in the spleen. EJI Highlight 2006; 36:1.

Gaffal E, Schweichel D, Tormo D, Steitz J, Lenz J, Basner-Tschakarjan E, Limmer A, Tuting T. Comparative evaluation of CD8+CTL responses following gene gun immunization targeting the skin with intracutaneous injection of antigen-transduced dendritic cells. Eur J Cell Biol. 2006; [Epub ahead of print].

Wingender G, Berg M, Jüngerkes F, Sullivan BA, Kronenberg M, Limmer A and Knolle PA: Immediate antigen-specific effector functions by TCR transgenic NKT cells. EJI 2006; 36: 570.

Schweichel D, Steitz J, Tormo D, Gaffal E, Ferrer A, Buechs S, Speuser P, Limmer A and Tueting T. Evaluation of DNA vaccination with recombinant adenoviruses using bioluminescence imaging of antigen expression: Impact of application routes and delivery with dendritic cells. J. Gene Med 2006;8: 1243.

Basner-Tschakarjan E, Gaffal E, Steitz J, Lenz J, Schweichel D, Tormo D, Ferrer A, Büchs S, Speuser P, Limmer A and Tüting T: The epidermis represents an immunological barrier for the induction of CD8+ cytotoxic T cell response: Lessons from cutaneous DNA vaccination studies. J Gene Med. 2006 Nov;8:1300.

Limmer A, Ohl J, Wingender G, Berg M, Jüngerkes F, Schumak B, Djandji D, Scholz K, Klevenz A, Hegenbarth S, Momburg F, Hämmerling GJ, Arnold B and Knolle PA: Cross-presentation of oral antigens by liver sinusoidal endothelial cells leads to CD8 T cell tolerance. Eur J Immunol. 2005;35:2970.

Wingender G, Schumak B, Schurich A, Gessner JE, Endl E, Limmer A and Knolle PA: Rapid and preferential distribution of blood-borne ?CD3?Ab to the liver is followed by local stimulation of T and NKT cells. Immunology. 2006 Jan;117:117.

Limmer A, Ganss R, Garbi N, Arnold B, Hammerling GJ. Stimulation of autoimmunity by toll-like receptor ligands. Ann Rheum Dis. 2005; 64:Suppl 4:iv15-7. Review.

Uhrig A, Banafsche R, Kremer M, Hegenbarth S, HamannA, Neurath M, Gerken G, Limmer A and Knolle PA: Development and functional consequences of LPS tolerance in sinusoidal endothelial cells of the liver. J. Leukoc. Biol 2005 ; 77: 626-633.

Feuerer M, Beckhove, P., Garbi, N., Mahnke, Y., Limmer, A., Hommel, M., Hammerling, G. J., Kyewski, B., Hamann, A., Umansky, V., and Schirrmacher, V.: Bone marrow as a priming site for T-cell responses to blood-borne antigen. Nat Med 2003; 9: 1151-1157.

Weber, O., Siegling, A., Friebe, A., Limmer, A., Schlapp, T., Knolle, P., Mercer, A., Schaller, H., and Volk, H. D: Inactivated parapoxvirus ovis (Orf virus) has antiviral activity against hepatitis B virus and herpes simplex virus. J Gen Virol 2003; 84, 1843-1852.

Knolle, P. A., and Limmer, A.: Control of immune responses by savenger liver endothelial cells. Swiss Med Wkly 2003; 133, 501-506.

Sacher T, Knolle PA, Nichterlein T, Arnold B, Hämmerling GJ, Limmer A.: CpG-ODN-ODN-induced inflammation is sufficient to cause T-cell-mediated autoaggression against hepatocytes. Eur  J Immunol 2002 ; 32 :3628-3637.

Knolle PA, Limmer A: Neighborhood politics: Immunoregulatory function of organ-resident liver endothelial cells. Trends Immunol. 2001 Aug. (22): 432-436.

Limmer A, Ohl J, Kurts C, Ljunggren HG, Reiss Y, Groettrup M, Momburg F, Arnold B, Knolle PA. Efficient presentation of exogenous antigen by liver endothelial cells to CD8+ T cells results in antigen-specific T-cell tolerance. Nat Med. 2000; 6:1348-54.

Ganss R, Limmer A, Sacher T, Arnold B, Hammerling GJ. Autoaggression and tumor rejection: it takes more than self-specific T-cell activation. Immunol  Rev. 1999 Jun; 169:263-72. Review.

Limmer A, Sacher T, Alferink J, Nichterlein T, Arnold B, Hammerling GJ.: A two-step model for the induction of organ-specific autoimmunity. Novartis Found Symp. 1998; 215:159-67; discussion 167-71, 186-90.

Limmer A, Sacher T, Alferink J, Kretschmar M, Schonrich G, Nichterlein T, Arnold B, Hammerling GJ. Failure to induce organ-specific autoimmunity by breaking of tolerance: importance of the microenvironment. Eur J Immunol. 1998 Aug;28(8):2395-406.