The immune system has evolved over time to defeat external threats such as bacteria and viruses, as well as internal threats like cancer. The ability of the immune system to destroy such a diverse number of invaders is a tribute to its robustness. However, this comes at a price and its complexity can result in severe complications.

In some diseases, such as autoimmune diseases and chronic inflammation, the immune system actually contributes through a misdirected immune response. In other diseases, such as cancer or chronic infections, an insufficient immune response leads to disease progression. More recently, misguided or deregulated immune responses have been implicated in non-classical immune disorders such as obesity, cardiovascular diseases, and fibrosis.

Understanding complex immune responses and their switch points in the tissue context is crucial to manipulating immune reactions in a tissue-targeted manner. And it is precisely at the interface of where these switch points occur that the Research Division Immunology focuses its efforts. Inflammation and tissue regeneration are connected processes within tissues. An important function, in this context, is the ability of specialized immune cells, such as regulatory T cells (Treg cells), to direct local immune responses, as well as to organize tissue repair and tissue homeostasis. To induce tissue-regeneration processes, immune cells have to communicate with tissue-resident cells such as tissue stem cells, epithelial cells, fibroblasts, and other tissue-immune cells. This tissue-immune communication leading to tissue regeneration is likely highly relevant in understanding cancer progression and metastasis.

Research into immune cell functions in tissues such as regeneration and organ homeostasis is still in its infancy. To this day, we have limited understanding of important molecular mechanisms and interaction partners. But the Research Division Immunology is looking to change that.

Single cell ATAC-sequencing analysis of CD4 T cells located in different tissues

The goal is to develop targeted therapeutic manipulation of different aspects of tissue immunology. These aspects include: tissue-located immune cell differentiation; tissue-immune communication; wound healing triggered by immune cells, and tissue homeostasis supported by immune cells. This research will enable the development of tailored immunotherapies for the treatment of chronic inflammation, autoimmune diseases, and transplant rejection. Such interventions will also be applicable in the treatment of cancer.

To explore how regulatory mechanisms can be exploited in an immunotherapeutic way, the Research Division Immunology is on a mission to develop new artificial immune networks. Using synthetic immunology tools, we seek to transfer the basic findings about targets and mechanisms into novel immunotherapies through the generation of engineered immune cells. The aim is to engineer immune cells to be more flexible in their recognition of targets and enhance their functionality within the tissues.

Regulatory T cells

The self-regulation of the immune system is mediated by a specialized immune cell population known as regulatory T cells (Treg). These Treg cells are able to monitor other immune cells and reduce their activity. In addition, a specialized subset of Treg cells, known as ‘tissue-Treg cells’ and located in organs and tissues, can contribute to tissue regeneration, homeostasis, and healing of injuries. The Research Division Immunology aims to better understand the tissue-type differentiation and their function (Delacher et al. Nature Immunology, 2017). The differentiation into the tissue-Treg phenotype starts in precursors in lymphoid organs and ends in the tissues (Delacher et al. Immunity, 2020). We recently characterized human tissue-Treg cells on a molecular level (Delacher et al. Immunity, 2021). In our ongoing research, we are investigating how these cells contribute to homeostasis and tissue regeneration. We are also examining which factors, molecules, and mechanisms are used to communicate with tissue cells to trigger the regeneration processes.

A variety of modern technologies and different experimental systems are in place to study populations of Treg cells. These include epigenetic and single-cell sequencing technologies, genome editing methods, and different 3D organoid model systems. In vivo and in vitro model systems are also used to study therapeutic intervention in cancer, Graft-versus-Host-Disease (GvHD) and chronic inflammation.

Treg cells accumulate in an early lung metastasis lesion (Foxp3, dark brown nuclei stain)

Communication between tissue and immune cells

Our body’s tissues consist of various different cells. One important component is the immune cells which influence other tissue cells and also play a role in tissue remodeling. They communicate in different ways with tissue-resident cells such as fibroblasts, epithelial cells, and tissue stem cells. Some, for example, produce different messenger substances which act on these tissue cells and lead to changes in cell-to-cell communication, cell differentiation, and cell growth. But tissue cells can also influence the function of tissue-resident immune cells and thus control immune responses.

Consequently, both immune and tissue cells—and their interactions—work in symbiosis in times of inflammation and are critical in the maintenance and re-establishment of tissue homeostasis and wound healing. Of course, if that balance is disturbed, various diseases may occur. For example, a deregulation of fibroblasts can lead to uncontrolled wound healing and fibrotic diseases, as well as tumor growth and metastasis.

In fact, so-called ‘tumor-associated fibroblasts’ have been found to have a contributory effect in tumor growth. This happens when they create an environment that promotes tumor-cell proliferation and metastasis formation, while inhibiting the anti-tumor activity of the immune system. Our ongoing research will investigate tissue-to-immune cell communication, and also focus on immune cell-to-fibroblast and immune cell-to-epithelial interactions.

Model of epithelial cell, fibroblast, and T-cell communication

Synthetic Immunology and artificial immune receptors

Synthetic Immunology is the artificial design of synthetic systems that are able to perform novel immunological functions. With this in mind, the Research Division’s focus is on the design of new artificial signaling networks that either allow new immunological functions to be implemented in immune cells or reprogram immune cells so that they can perform new functions for cellular immunotherapy.

We have two specific objectives: Firstly, we are seeking to generate synthetic genetic modules to instruct Treg cells to control inflammation and support tissue regeneration. Secondly, we are seeking to strengthen effector T cells to better combat cancer. A good example of this is a project we are running focused on using artificial immune receptors as novel biosensors (Bittner et al. PNAS, 2022; Bittner et al. Trends in Immunology, 2023). Here, artificial sensors are developed to help Treg cells sense inflammation better and fight it more effectively. To this end, Treg cells are reprogrammed and equipped with new functionality with the goal of developing innovative therapeutic concepts for the treatment of inflammatory diseases.

We shine the spotlight on this special research project. For more information click here to visit the page “Featured Project – AIR Treg cells”!

AIR-Treg cell therapy concept for treatment of inflammatory and autoimmune diseases (Figure created with BioRender)

Myeloid Cell-Driven Immunoregulation

This Sub-Group within the Research Division Immunology focuses on so-called skin-associated lymphatic tissue (SALT). Its focus is to investigate how antigen-specific immune responses are both induced and regulated in skin-draining lymph nodes. In this context, we concentrate on myeloid cells and adaptive immune responses resulting from interactions between antigen-presenting cells and T cells.

Currently, we seek to characterize the cellular checkpoints that result in the initiation and regulation of T cell-mediated immunity. Of particular interest, is the impact of myeloid subsets in immune regulation and wound healing.

Our goal is to identify exogenous and endogenous mediators that are interfering with checkpoints in immunoregulation. We seek to modulate these immune checkpoints in order to cure immunopathological manifestations such as autoimmune diseases.

Three-dimensional visualization of physically interacting immune cells. Color code: nuclei = blue, T cells = yellow, dendritic cells = red, overlapping membranes = gray

A) Immunomodulation by microbial components

Our immune system is in permanent contact with the body’s specific bacterial milieu. Such bacteria, also known as commensal bacteria, are important for healthy skin to function optimally as a barrier. Under certain circumstances, however, some commensal bacteria can develop resistance to antibiotics and cause fulminant infections.

The aim of this research project is to understand why our immune system detects but tolerates commensal skin bacteria such as Staphylococcus epidermidis, without inducing active defense mechanisms. Our intention is to seek to overcome this immunotolerance in order to achieve protective immune responses against multi-resistant bacteria.

The specific modulation of these tolerance-mediating triggers is also relevant for the development of new targets against chronic autoimmune and tumor diseases.

This project is funded by the Bavarian Ministry of Science and the Arts within the framework of the Bavarian Research Network: ‘New Strategies Against Multi-Resistant Pathogens by Means of Digital Networking’ (bayresq.net).

These findings will help us to further clarify the origin and outcome of adaptive immune responses. In addition, myeloid cells with chimeric antigen receptors (CARs) will be developed. CAR-DCs and CAR-macrophages will be used for the acceleration or attenuation of immunopathological processes. These aspects will play a central role in clinical applications where T-cell responses are induced (e.g. vaccination) or modulated (e.g. autoimmunity).

B) Myeloid cells and adaptive immunity

SALT is composed of the following main components:

A complex group of myeloid cell subtypes capable of processing and presenting skin-derived antigens (foreign or self).
Skin-draining lymph nodes that respond to cutaneous antigens.
A wide range of specialized T and B lymphocytes with different functions.

In this context we are particularly interested in the characterization of dermal-derived antigens within skin-draining lymph nodes. We will specifically detect and analyze migratory dermal cells within skin-draining lymph nodes, using various mouse models that the LIT has established.

Previous work has demonstrated that certain subtypes of dendritic cells (DC) can induce DC-specific immune responses against pathogens. Using cutting edge methods such as single-cell RNA sequencing and imaging techniques, we aim to decode the cellular mechanisms responsible for the dissection of commensal-derived or pathogen-derived immune responses.

For inquiries regarding Myeloid Cell-Driven Immunoregulation please contact:

Assoc. Prof. Uwe Ritter
Immunology Division | Myeloid Cell-Driven Immunoregulation

Tel: +49 941 944–18125
Email: uwe.ritter@ukr.de

Visit the complete list of our Research Division’s publications on Google Scholar:

https://scholar.google.de/citations?user=mx7YLIcAAAAJ&hl=dexxx

Here is a selection of the most important publications from the last few years:

Delacher M, Schmidleithner L, Simon M, Stüve P, Sanderink L, Hotz-Wagenblatt A, Wuttke M, Schambeck K, Ruhland B, Hofmann V, Bittner S, Ritter U, Pant A, Helbich SS, Voss M, Lemmermann NA, Bessiri-Schake L, Bohn T, Eigenberger A, Menevse AN, Gebhard C, Strieder N, Abken H, Rehli M, Huehn J, Beckhove P, Hehlgans T, Junger H, Geissler EK, Prantl L, Werner JM, Schmidl C, Brors B, Imbusch CD, Feuerer M. The effector program of human CD8 T cells supports tissue remodeling. J Exp Med. 2024 Feb 5;221(2):e20230488. doi: 10.1084/jem.20230488. Epub 2024 Jan 16. PMID: 38226976 Free PMC article.

Bittner S, Hehlgans T, Feuerer M. Engineered Treg cells as putative therapeutics against inflammatory diseases and beyond. Trends Immunol. 2023 Jun;44(6):468-483. doi: 10.1016/j.it.2023.04.005. Epub 2023 Apr 25. PMID: 37100644 Free article. Review..

Bittner S, Ruhland B, Hofmann V, Schmidleithner L, Schambeck K, Pant A, Stüve P, Delacher M, Echtenacher B, Edinger M, Hoffmann P, Rehli M, Gebhard C, Strieder N, Hehlgans T, Feuerer M. Biosensors for inflammation as a strategy to engineer regulatory T cells for cell therapy. Proc Natl Acad Sci U S A. 2022 Oct 4;119(40):e2208436119. doi: 10.1073/pnas.2208436119. Epub 2022 Sep 26. PMID: 36161919 Free PMC article.

Delacher M, Simon M, Sanderink L, Hotz-Wagenblatt A, Wuttke M, Schambeck K, Schmidleithner L, Bittner S, Pant A, Ritter U, Hehlgans T, Riegel D, Schneider V, Groeber-Becker FK, Eigenberger A, Gebhard C, Strieder N, Fischer A, Rehli M, Hoffmann P, Edinger M, Strowig T, Huehn J, Schmidl C, Werner JM, Prantl L, Brors B, Imbusch CD, Feuerer M. Single-cell chromatin accessibility landscape identifies tissue repair program in human regulatory T cells. Immunity. 2021 Apr 13;54(4):702-720.e17. doi: 10.1016/j.immuni.2021.03.007. Epub 2021 Mar 30. PMID: 33789089 Free PMC article.

Delacher M, Imbusch CD, Hotz-Wagenblatt A, Mallm JP, Bauer K, Simon M, Riegel D, Rendeiro AF, Bittner S, Sanderink L, Pant A, Schmidleithner L, Braband KL, Echtenachter B, Fischer A, Giunchiglia V, Hoffmann P, Edinger M, Bock C, Rehli M, Brors B, Schmidl C, Feuerer M. Precursors for Nonlymphoid-Tissue Treg Cells Reside in Secondary Lymphoid Organs and Are Programmed by the Transcription Factor BATF. Immunity. 2020 Feb 18;52(2):295-312.e11. doi: 10.1016/j.immuni.2019.12.002. Epub 2020 Jan 7. PMID: 31924477 Free PMC article.

Delacher M, Schmidl C, Herzig Y, Breloer M, Hartmann W, Brunk F, Kägebein D, Träger U, Hofer AC, Bittner S, Weichenhan D, Imbusch CD, Hotz-Wagenblatt A, Hielscher T, Breiling A, Federico G, Gröne HJ, Schmid RM, Rehli M, Abramson J, Feuerer M. Rbpj expression in regulatory T cells is critical for restraining T_H2 responses. Nat Commun. 2019 Apr 8;10(1):1621. doi: 10.1038/s41467-019-09276-w. PMID: 30962454 Free PMC article

Delacher M, Imbusch CD, Weichenhan D, Breiling A, Hotz-Wagenblatt A, Träger U, Hofer AC, Kägebein D, Wang Q, Frauhammer F, Mallm JP, Bauer K, Herrmann C, Lang PA, Brors B, Plass C, Feuerer M. Corrigendum: Genome-wide DNA-methylation landscape defines specialization of regulatory T cells in tissues. Nat Immunol. 2017 Nov 16;18(12):1361. doi: 10.1038/ni1217-1361b. PMID: 29144491

Richards DM, Kyewski B, Feuerer M. Re-examining the Nature and Function of Self-Reactive T cells. Trends Immunol. 2016 Feb;37(2):114-125. doi: 10.1016/j.it.2015.12.005. Epub 2016 Jan 12. PMID: 26795134 Free PMC article. Review.

Hettinger J, Richards DM, Hansson J, Barra MM, Joschko AC, Krijgsveld J, Feuerer M. Origin of monocytes and macrophages in a committed progenitor. Nat Immunol. 2013 Aug;14(8):821-30. doi: 10.1038/ni.2638. Epub 2013 Jun 30. PMID: 23812096

Feuerer M, Shen Y, Littman DR, Benoist C, Mathis D. How punctual ablation of regulatory T cells unleashes an autoimmune lesion within the pancreatic islets. Immunity. 2009 Oct 16;31(4):654-64. doi: 10.1016/j.immuni.2009.08.023. Epub 2009 Oct 8. PMID: 19818653 Free PMC article.

Feuerer M, Herrero L, Cipolletta D, Naaz A, Wong J, Nayer A, Lee J, Goldfine AB, Benoist C, Shoelson S, Mathis D. Lean, but not obese, fat is enriched for a unique population of regulatory T cells that affect metabolic parameters. Nat Med. 2009 Aug;15(8):930-9. doi: 10.1038/nm.2002. Epub 2009 Jul 26. PMID: 19633656 Free PMC article.

Feuerer M, Hill JA, Mathis D, Benoist C. Foxp3+ regulatory T cells: differentiation, specification, subphenotypes. Nat Immunol. 2009 Jul;10(7):689-95. doi: 10.1038/ni.1760. PMID: 19536194 Review.

Feuerer M, Beckhove P, Garbi N, Mahnke Y, Limmer A, Hommel M, Hämmerling GJ, Kyewski B, Hamann A, Umansky V, Schirrmacher V. Bone marrow as a priming site for T-cell responses to blood-borne antigen. Nat Med. 2003 Sep;9(9):1151-7. doi: 10.1038/nm914. Epub 2003 Aug 10. PMID: 12910264

Feuerer M, Beckhove P, Bai L, Solomayer EF, Bastert G, Diel IJ, Pedain C, Oberniedermayr M, Schirrmacher V, Umansky V. Therapy of human tumors in NOD/SCID mice with patient-derived reactivated memory T cells from bone marrow. Nat Med. 2001 Apr;7(4):452-8. doi: 10.1038/86523. PMID: 11283672

Here is a selection of the most important publications of ‘Myeloid Cell-Driven Immunoregulation‘:

Delacher M, Simon M, Sanderink L, Hotz-Wagenblatt A, Wuttke M, Schambeck K, Schmidleithner L, Bittner S, Pant A, Ritter U, Hehlgans T, Riegel D, Schneider V, Groeber-Becker FK, Eigenberger A, Gebhard C, Strieder N, Fischer A, Rehli M, Hoffmann P, Edinger M, Strowig T, Huehn J, Schmidl C, Werner JM, Prantl L, Brors B, Imbusch CD, Feuerer M. Single-cell chromatin accessibility landscape identifies tissue repair program in human regulatory T cells. Immunity. 2021 Apr 13;54(4):702-720.e17. doi: 10.1016/j.immuni.2021.03.007. Epub 2021 Mar 30. PMID: 33789089 Free PMC article.

Ribechini E, Eckert I, Beilhack A, Du Plessis N, Walzl G, Schleicher U, Ritter U, Lutz MB. Heat-killed Mycobacterium tuberculosis prime-boost vaccination induces myeloid-derived suppressor cells with spleen dendritic cell-killing capability. JCI Insight. 2019 Jun 4;5(13):e128664. doi: 10.1172/jci.insight.128664. PMID: 31162143 Free PMC article.

Zimara N, Chanyalew M, Aseffa A, van Zandbergen G, Lepenies B, Schmid M, Weiss R, Rascle A, Wege AK, Jantsch J, Schatz V, Brown GD, Ritter U. Dectin-1 Positive Dendritic Cells Expand after Infection with Leishmania major Parasites and Represent Promising Targets for Vaccine Development. Front Immunol. 2018 Feb 26;9:263. doi: 10.3389/fimmu.2018.00263. eCollection 2018. PMID: 29535708 Free PMC article.

Blazquez R, Wlochowitz D, Wolff A, Seitz S, Wachter A, Perera-Bel J, Bleckmann A, Beißbarth T, Salinas G, Riemenschneider MJ, Proescholdt M, Evert M, Utpatel K, Siam L, Schatlo B, Balkenhol M, Stadelmann C, Schildhaus HU, Korf U, Reinz E, Wiemann S, Vollmer E, Schulz M, Ritter U, Hanisch UK, Pukrop T. PI3K: A master regulator of brain metastasis-promoting macrophages/microglia. Glia. 2018 Nov;66(11):2438-2455. doi: 10.1002/glia.23485. Epub 2018 Oct 25. PMID: 30357946

Brand A, Singer K, Koehl GE, Kolitzus M, Schoenhammer G, Thiel A, Matos C, Bruss C, Klobuch S, Peter K, Kastenberger M, Bogdan C, Schleicher U, Mackensen A, Ullrich E, Fichtner-Feigl S, Kesselring R, Mack M, Ritter U, Schmid M, Blank C, Dettmer K, Oefner PJ, Hoffmann P, Walenta S, Geissler EK, Pouyssegur J, Villunger A, Steven A, Seliger B, Schreml S, Haferkamp S, Kohl E, Karrer S, Berneburg M, Herr W, Mueller-Klieser W, Renner K, Kreutz M. LDHA-Associated Lactic Acid Production Blunts Tumor Immunosurveillance by T and NK Cells. Cell Metab. 2016 Nov 8;24(5):657-671. doi: 10.1016/j.cmet.2016.08.011. Epub 2016 Sep 15. PMID: 27641098 Free article.

Schatz V, Strüssmann Y, Mahnke A, Schley G, Waldner M, Ritter U, Wild J, Willam C, Dehne N, Brüne B, McNiff JM, Colegio OR, Bogdan C, Jantsch J. Myeloid Cell-Derived HIF-1α Promotes Control of Leishmania major. J Immunol. 2016 Nov 15;197(10):4034-4041. doi: 10.4049/jimmunol.1601080. Epub 2016 Oct 17. PMID: 27798163 Free PMC article.

Horst AK, Bickert T, Brewig N, Ludewig P, van Rooijen N, Schumacher U, Beauchemin N, Ito WD, Fleischer B, Wagener C, Ritter U. CEACAM1+ myeloid cells control angiogenesis in inflammation. Blood. 2009 Jun 25;113(26):6726-36. doi: 10.1182/blood-2008-10-184556. Epub 2009 Mar 9. PMID: 19273835 Free article.

Brewig N, Kissenpfennig A, Malissen B, Veit A, Bickert T, Fleischer B, Mostböck S, Ritter U. Priming of CD8+ and CD4+ T cells in experimental leishmaniasis is initiated by different dendritic cell subtypes. J Immunol. 2009 Jan 15;182(2):774-83. doi: 10.4049/jimmunol.182.2.774. PMID: 19124720

Ritter U, Osterloh A. A new view on cutaneous dendritic cell subsets in experimental leishmaniasis. Med Microbiol Immunol. 2007 Mar;196(1):51-9. doi: 10.1007/s00430-006-0023-0. Epub 2006 Jun 20. PMID: 16786361 Review.

Ritter U, Meissner A, Scheidig C, Körner H. CD8 alpha- and Langerin-negative dendritic cells, but not Langerhans cells, act as principal antigen-presenting cells in leishmaniasis. Eur J Immunol. 2004 Jun;34(6):1542-50. doi: 10.1002/eji.200324586. PMID: 15162423 Free article.

Here are some of the partners with whom the Research Division has recently collaborated:

CRC/TR 221

The Collaborative Research Center, Transregio (CRC/TR) 221 funded by the Deutsche Forschungsgemeinschaft (German Research Foundation) investigates innovative immune-modulation strategies to separate graft-versus-host disease from graft-versus-leukemia effects. This seeks to enhance the safety and efficacy of allogeneic hematopoietic stem cell transplantation (HSCT) in the future. Led by Prof Feuerer, the project aims to harness the function of regulatory T cells to promote tissue homeostasis in graft-versus-host disease (Project B08).

https://www.gvhgvl.de/en/projects-publications/projects/project-section-b

CRC/TR 305

The Collaborative Research Center, Transregio (CRC/TR) 305 is funded by the Deutsche Forschungsgemeinschaft (German Research Foundation) and is entitled “Striking a Moving Target: From Mechanisms of Metastatic Organ Colonization to Novel Systemic Therapies”. Together with Prof. Hehlgans, Prof. Feuerer is studying the functional role of fibroblast-derived IL-33 in early metastasis (Project B06).

https://www.trr305.de/en/projects

The Bavarian Research Network
New Strategies Against Multi-Resistant Pathogens by Means of Digital Networking

This project aims to identify commensal bacteria-associated immune checkpoints as novel targets for immunotherapy against multidrug-resistant Staphylococcus Epidermidis strains.

https://bayresq.net/en/projekte-iris-en/

Many thanks to the funding agencies who support our work:

DFG: Collaborative Research Center, Transregio (CRC/TR) 221
https://www.gvhgvl.de/

DFG: Collaborative Research Center, Transregio (CRC/TR) 305
https://www.trr305.de/en/

Bavarian Research Network – IRIS
https://bayresq.net/en/projekte-iris-en/

Prof. Markus Feuerer

Deputy Scientific Director LIT
Head of Research Division | Immunology

Tel: +49 941 944–38121
Email: markus.feuerer@lit.eu

Luise Eder

Team Assistant

Tel: +49 941 944–38122
Email: luise.eder@ukr.de

Research team

Prof. Markus Feuerer

Deputy Scientific Director LIT & Head of Research Division | Immunology

Assoc. Prof. Uwe Ritter

Immunology Division | Myeloid Cell-Driven Immunoregulation

Dr. Sebastian Bittner

Postdoctoral Scientist

Dr. Philipp Stüve

Postdoctoral Scientist

Dr. Lisa Schmidleithner

Postdoctoral Scientist

Frauke Hoffmann

PhD Student

Lorenz Kohler

PhD Student

Ardita Ramadani

PhD Student

Brigitte Ruhland

Research Technician

Marina Wuttke

Research Technician

Kathrin Gütter

Research Technician

Veronika Hofmann

Research Technician

Lab Life

There is life outside the laboratory: The Leibniz Institute places great value on our scientists developing the team spirit both in and out of work. Here are the photos to prove it!