Research foci Infection Immunology
As dendritic cells (DCs) are the major players initiating T cell responses and influencing T cell differentiation, the scientists of the Institute of Infection Immunology study the first steps of host-pathogen interaction at the DC level in various bacterial, viral and fungal infection models. DCs are part of the innate immune system that recognize microbial-associated molecular patterns (MAMPs) from pathogens via pattern recognition receptors (PRRs) and are at present crucial target cells for vaccination. Their previous work has led to the discovery of several MAMPs and, in part, their introduction into the clinic as new potent adjuvants. Using novel genetic models (BAC, CRISPR/Cas9 technology) the researchers try to address the following questions: Which roles do the various and highly-specialized sub-types of DCs play in different infections? What significance do certain pattern recognition receptors have for DC activation, antigen uptake and the corresponding T cell responses? How can they exploit this knowledge for more specific, safer adjuvants and better DC targeting approaches?
T effector cell immunomodulation
An immune response to microbes and vaccines is initiated when a dendritic cell (DC) takes up an antigen, becomes activated and presents it to naïve (CD4+) T helper (Th) cells. Th cells begin to proliferate and differentiate into specialized Th subsets (e.g. pro-inflammatory Th1, Th2, Th9, Th17 or anti-inflammatory regulatory T cells – Tregs) which help to establish humoral or cellular immunity or tolerance. Due to their central role in this multistep process, T cells are known to be at the core of immunological effector mechanisms. Defining new biomarkers for specific immune reactions will be extremely valuable for diagnostics and therapy. Since T cells are not only responsible for controlling tumor cells and pathogens, but also provide important mechanisms of tissue repair, the scientists mainly focus on T cells and the direct and indirect impact of microbial factors on T cell-mediated immunity as a central and unifying theme of their work.
Induction / inhibition of regulatory T cells
Controlling an immune response is just as crucial and this is where regulatory T cells (Tregs) play an exceedingly important role. On the one hand, they protect from overshooting immune responses and can prevent immunopathology, for example during chronic infections, allergy and autoimmune reactions. In the future, adoptive transfer of patient-derived Tregs could therefore represent an essential aspect of individualized infection medicine. On the other hand, Tregs may be exploited by certain pathogens as they are induced during e.g. mycobacterial and certain viral infections and prevent pathogen clearance. In addition, there is strong evidence that Tregs inhibit tumor rejection. An optimal vaccination approach should incorporate strategies that would activate DCs and prevent Tregs from slowing down an adequate immune reaction without inducing autoimmunity.
Deciphering the human microbiome was thought to offer novel diagnostic and therapeutic avenues for almost any chronic illness of the ageing European society, a premature hope as the complexity of the microbiome is surpassed by the complexity of the metabolites produced by various commensals and pathogens. Understanding the metabolome, the ‘molecular language’ between microbiota and their mammalian hosts, may offer mechanistic clues as to how bacteria influence our immune system and contribute to inflammation and tolerance, reflecting one of the biggest challenges for future research. There are strong indications that the microbial metabolome, which is extremely diverse and remains largely undefined, will provide a tremendous arsenal of new powerful immune modulators.
Friedrich, C., Mamareli. P., Thiemann, S., Kruse, F., Wang, Z., Holzmann, B., Strowig, T., Sparwasser, T. and M. Lochner. 2017. MyD88 signaling in dendritic cells and the intestinal epithelium controls immunity against intestinal infection with C. rodentium. PLOS Pathogens 13(5): 1-26.
Puttur, F., M. Francozo, G. Solmaz, C. Bueno, M. Lindenberg, M. Gohmert, M. Swallow, D. Tufa, R. Jacobs, S. Lienenklaus, A.A. Kühl, L. Borkner, L. Cicin-Sain, B. Holzmann, H. Wagner, L. Berod and T. Sparwasser. 2016. Conventional Dendritic Cells Confer Protection Against Mouse Cytomegalovirus Infection via TLR9 and MyD88 Signaling. Cell Reports 17(4): 1113 - 1127.
Dudek, M., F. Puttur, C. Arnold-Schrauf, A.A. Kuhl, B. Holzmann, B. Henriques-Normark, L. Berod, and T. Sparwasser. 2016. Lung epithelium and myeloid cells cooperate to clear acute pneumococcal infection. Mucosal Immunology Sep;9(5):1288-302.
Mayer, C.T., P. Ghorbani, A. Nandan, M. Dudek, C. Arnold-Schrauf, C. Hesse, L. Berod, P. Stuve, F. Puttur, M. Merad, and T. Sparwasser. 2014. Selective and efficient generation of functional Batf3-dependent CD103+ dendritic cells from mouse bone marrow. Blood 124:3081-3091.
Arnold-Schrauf, C., M. Dudek, A. Dielmann, L. Pace, M. Swallow, F. Kruse, A.A. Kuhl, B. Holzmann, L. Berod, and T. Sparwasser. 2014. Dendritic cells coordinate innate immunity via MyD88 signaling to control Listeria monocytogenes infection. Cell Reports 6:698-708
Puttur, F., C. Arnold-Schrauf, K. Lahl, G. Solmaz, M. Lindenberg, C.T. Mayer, M. Gohmert, M. Swallow, C. van Helt, H. Schmitt, L. Nitschke, B.N. Lambrecht, R. Lang, M. Messerle, and T. Sparwasser. 2013. Absence of Siglec-H in MCMV infection elevates interferon alpha production but does not enhance viral clearance. PLoS Pathogens 9:e1003648.
Funding: DFG (SFB 900), Boehringer Ingelheim Fonds, DAAD, FAPESP - The São Paulo Research Foundation, Fundação para a Ciência e Tecnologia, Ciência sem fronteiras, Volkswagen Foundation (Israel/Germany), DZIF
T effector cell immunomodulation
Yang BH, Hagemann S, Mamareli P, Lauer U, Hoffmann U, Beckstette M, Fohse L, Prinz I, Pezoldt J, Suerbaum S, Sparwasser T, Hamann A, Floess S, Huehn J, Lochner M (2016) Foxp3(+) T cells expressing RORgammat represent a stable regulatory T-cell effector lineage with enhanced suppressive capacity during intestinal inflammation. Mucosal Immunol 9(2): 444-457.
Yang BH, Floess S, Hagemann S, Deyneko IV, Groebe L, Pezoldt J, Sparwasser T, Lochner M, Huehn J (2015) Development of a unique epigenetic signature during in vivo Th17 differentiation. Nucleic Acids Res 43(3): 1537-1548.
Lochner M, Wang Z, Sparwasser T (2015) The Special Relationship in the Development and Function of T Helper 17 and Regulatory T Cells. Prog Mol Biol Transl Sci 136: 99-129.
Berod L, Friedrich C, Nandan A, Freitag J, Hagemann S, Harmrolfs K, Sandouk A, Hesse C, Castro CN, Bahre H, Tschirner SK, Gorinski N, Gohmert M, Mayer CT, Huehn J, Ponimaskin E, Abraham WR, Muller R, Lochner M, Sparwasser T (2014) De novo fatty acid synthesis controls the fate between regulatory T and T helper 17 cells. Nat Med 20(11): 1327-1333.
Wang Z, Friedrich C, Hagemann SC, Korte WH, Goharani N, Cording S, Eberl G, Sparwasser T, Lochner M (2014) Regulatory T cells promote a protective Th17-associated immune response to intestinal bacterial infection with C. rodentium. Mucosal Immunol 7(6): 1290-1301.
Wilhelm C, Hirota K, Stieglitz B, Van Snick J, Tolaini M, Lahl K, Sparwasser T, Helmby H, Stockinger B (2011) An IL-9 fate reporter demonstrates the induction of an innate IL-9 response in lung inflammation. Nat Immunol 12(11): 1071-1077.
Funding: DFG (SFB 900, KFO 250, LO 1415/7-1), EU (Marie Curie ITN fellowship), Volkswagen Foundation (CDIFF), HSBDR, COALITION
Induction / inhibition of regulatory T cells
Yang, B.H., Hagemann, S., Mamareli, P., Lauer, U., Hoffmann, U., Beckstette, M., Föhse, L., Prinz, I., Pezoldt, J., Suerbaum, S., Sparwasser, T., Hamann, A., Floess, S., Huehn, J. and M. Lochner. 2016. Foxp3 T cells expressing RORgammat represent a stable regulatory T-cell effector lineage with enhanced suppressive capacity during intestinal inflammation. Mucosal Immunol 9(2): 444-457.
Berod, L., P. Stuve, F. Varela, J. Behrends, M. Swallow, F. Kruse, F. Krull, P. Ghorbani, C.T. Mayer, C. Holscher, and T. Sparwasser. 2014. Rapid rebound of the Treg compartment in DEREG mice limits the impact of Treg depletion on mycobacterial burden, but prevents autoimmunity. PLoS One 9:e102804.
Berod, L., C. Friedrich, A. Nandan, J. Freitag, S. Hagemann, K. Harmrolfs, A. Sandouk, C. Hesse, C.N. Castro, H. Bahre, S.K. Tschirner, N. Gorinski, M. Gohmert, C.T. Mayer, J. Huehn, E. Ponimaskin, W.R. Abraham, R. Muller, M. Lochner, and T. Sparwasser. 2014. De novo fatty acid synthesis controls the fate between regulatory T and T helper 17 cells. Nature Medicine. 20(11): 1327-33
Mayer, C.T., J. Huntenburg, A. Nandan, E. Schmitt, N. Czeloth, and T. Sparwasser. 2013. CD4 blockade directly inhibits mouse and human CD4(+) T cell functions independent of Foxp3(+) Tregs. J Autoimmun 47:73-82.
Pace, L., A. Tempez, C. Arnold-Schrauf, F. Lemaitre, P. Bousso, L. Fetler, T. Sparwasser, and S. Amigorena. 2012. Regulatory T cells increase the avidity of primary CD8+ T cell responses and promote memory. Science 338:532-536.
Beyer, M., Y. Thabet, R.U. Muller, T. Sadlon, S. Classen, K. Lahl, S. Basu, X. Zhou, S.L. Bailey-Bucktrout, W. Krebs, E.A. Schonfeld, J. Bottcher, T. Golovina, C.T. Mayer, A. Hofmann, D. Sommer, S. Debey-Pascher, E. Endl, A. Limmer, K.L. Hippen, B.R. Blazar, R. Balderas, T. Quast, A. Waha, G. Mayer, M. Famulok, P.A. Knolle, C. Wickenhauser, W. Kolanus, B. Schermer, J.A. Bluestone, S.C. Barry, T. Sparwasser, J.L. Riley, and J.L. Schultze. 2011. Repression of the genome organizer SATB1 in regulatory T cells is required for suppressive function and inhibition of effector differentiation. Nature Immunology 12:898-907.
Funding: DFG (SFB 900, IRTG 1273), Wilhelm-Sander-Stiftung, COALITION
Minarrieta, L., Ghorbani, P., Sparwasser, T. and L. Berod. 2017. Metabolites: deciphering the molecular language between DCs and their environment. Semin Immunopathol 39(2): 177-198.
Almeida, L., Lochner, M., Berod, L. and T. Sparwasser. 2016. Metabolic pathways in T cell activation and lineage differentiation. Semin Immunol 28(5): 514 - 524.
Raha, S., Raud, B., Oberdörfer, L., Castro, C.N., Schreder, A., Freitag, J., Longerich, T., Lochner, M., Sparwasser, T., Berod, L., Koenecke, C. and I. Prinz. 2016. Disruption of de novo fatty acid synthesis via acetyl-CoA carboxylase 1 inhibition prevents acute graft-versus-host disease. Eur J Immunol 46(9): 2233-2238.
Freitag J., L. Berod, T. Kamradt, T. Sparwasser. 2016. Immunometabolism and autoimmunity. Immunol Cell Biol 94(10): 925-934
Berod, L., and T. Sparwasser. 2016. pDCs take a deep breath to fight viruses. Immunity 44(6): 1246-1248.
Berod, L., C. Friedrich, A. Nandan, J. Freitag, S. Hagemann, K. Harmrolfs, A. Sandouk, C. Hesse, C.N. Castro, H. Bahre, S.K. Tschirner, N. Gorinski, M. Gohmert, C.T. Mayer, J. Huehn, E. Ponimaskin, W.R. Abraham, R. Muller, M. Lochner, and T. Sparwasser. 2014. De novo fatty acid synthesis controls the fate between regulatory T and T helper 17 cells. Nature Medicine 20(11): 1327-33
Castro, C.N., J. Freitag, L. Berod, M. Lochner, and T. Sparwasser. 2015. Microbe-associated immunomodulatory metabolites: Influence on T cell fate and function. Mol Immunol 68:575-584.
Lochner, M., L. Berod, and T. Sparwasser. 2015. Fatty acid metabolism in the regulation of T cell function. Trends Immunol 36:81-91.
Funding: DFG (SFB 900, LO 1415/7-1), EU (Marie Curie ITN fellowship), HSBDR, DZIF, COALITION