Immune Regulation

Prof. Dr. Markus Feuerer

Address

Prof. Dr. Markus Feuerer

Devision for Immunology

LIT Leibniz Institut for Immunotherapy
University of Regensburg
Franz-Josef-Strauß-Allee 11
93053 Regensburg

Phone: +49-(0)941-944-38121
Fax: +49-(0)941-944-38123
Email: markus.feuerer(at)ukr.de

Research Focus

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 foreign invaders is a tribute to its flexibility. However, this comes at a price and the complexity can lead to severe diseases. In some diseases, such as autoimmune diseases and chronic inflammation, the immune system contributes to the disease through a misdirected immune response. In other diseases, such as cancer or chronic infections, an insufficient immune response leads to disease progression. In addition, misguided or deregulated immune responses have recently been implicated in non-classical immune disorders such as obesity, cardiovascular diseases, and fibrosis. 

Understanding the switching points of complex immune responses in the tissue context is crucial to be able to manipulate immune reactions in a tissue targeted manner. It is precisely at these switch-points that the Division of Immunology conducts its research. 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), 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 stem cells and differentiated tissue cells, such as epithelial cells and fibroblasts. This tissue-immune communication leading to tissue regeneration is probably also important for cancer progression and metastasis.

A deep understanding of tissue regeneration and organ homeostasis induced by immune cells is still in its infancy. Important molecular mechanisms as well as the interaction partners are still not well known. The Division of Immunology is therefore increasingly focusing on these issues.

Targeted therapeutic manipulation of tissue-immunology aspects, including tissue-resident immune cell differentiation, tissue-immune communication, wound healing and tissue homeostasis by immune cells, will enable the development of tailored immunotherapies for the treatment of chronic inflammation, autoimmune diseases, transplant rejection and for their blockade in the context of tumor diseases. To address the question of how regulatory mechanisms can be exploited in an immunotherapeutic way, we are pursuing the goal of developing new artificial immune networks. Using synthetic immunology tools, the Division of Immunology transfers the basic findings of new targets and mechanisms into novel immunotherapies by generating engineered immune cells. The aim is to engineer immune cells in a way that they are more flexible in their recognition and functional output, e.g., better support tissue regeneration or are more resistant to exhaustion.

 

Research Topic

Regulatory T cells

The self-regulation of the immune system is mediated by a specialized immune cell population: called regulatory T cells (Tregs cells). These Treg cells are able to monitor other immune cells and reduce their activity. In addition, a specialized subset of Treg cells called “tissue-Treg cells”, which are located in organs and tissues, can contribute to tissue regeneration, homeostasis and healing of injuries.

We aim 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 is finalized in the tissues (Delacher et al. Immunity, 2020). We recently characterized human tissue-Tregs on a molecular level. (Delacher et al. Immunity, 2021).

In our ongoing research, we are investigating how these cells contributing to homeostasis and tissue regeneration. Which factors, molecules and mechanisms are used to communicate with tissue cell to induce regeneration processes? A variety of modern technologies and different experimental systems are in place to study populations of Treg cells. Those include epigenetic and single cell sequencing technologies (e.g., single cell RNA-sequencing and single cell ATAC-sequencing, DNA-methylation analysis; Figures 1-2), genome editing methods such as CRISPR/CAS9, different 3D organoid model systems (Figure 3), as well as in-vivo and in-vitro model systems to study therapeutic intervention in cancer, transplantation, Graft-versus-Host-Disease (GvHD) and chronic inflammation.

Fig. 1: Single cell ATAC-sequencing data from tissue resident immune cells.
Fig. 2: Tagmentation-based whole-genome bisulfite sequencing of human T cells.
Fig. 3: 3D organoid model system of human bile duct (upper panel) and murine small intestine (lower panel).

Tissue-Immune-Communication

The tissues of our bodies consist of many different cells – one important component being immune cells which both influence tissue cells and play a role in tissue remodeling. They communicate with tissue resident cells, e.g. fibroblasts, epithelial cells and tissue stem cells in different ways – among others by producing different messenger substances, which act on these tissue cells and lead to changes in cell-cell communication, cell differentiation and cell growth (Figure 4). Conversely, tissue cells can also influence the function of tissue resident immune cells and thus control immune responses.  Consequently, immune and tissue cells and their interactions form an important interface during inflammation and are vital for the maintenance of tissue homeostasis and wound healing.

However, if the balance is disturbed, this can lead to various diseases. For example, a deregulation of fibroblasts can lead to uncontrolled wound healing, fibrotic diseases, as well as tumor growth and metastasis. In fact, so-called 'tumor-associated fibroblasts' have been described to have a supportive effect in tumor growth by creating an environment that promotes tumor cell proliferation and metastasis formation while inhibiting the anti-tumor activity of the immune system.

In our ongoing research, we are investigating tissue-immune-communication and focus on immune cell-fibroblast and immune cell-epithelial cell interactions (or cancer cells, which are frequently of epithelial origin).

Fig. 4: In-vitro interaction between fibroblasts, tumor cells and immune cells

Artificial Immune Receptors and Synthetic Immunology

Synthetic Immunology is the artificial design of synthetic systems that are able to perform novel immunological functions. We focus on the design of new artificial signaling networks that allow new immunological functions to be implemented in immune cells or re-program immune cells in a way that these cells can perform new functions for cellular immunotherapy.  In order to provide immune cells with new functions and to use them therapeutically, it is first necessary to identify and understand existing signaling networks and their individual components under conditions of immune homeostasis and under immune activation, e.g. inflammatory conditions.

Using the methods of synthetic immunology, we specifically interfere with these processes, equip immune cells with artificial sensors, functions and control programs in order to modify them for cellular therapies. We have two aims, (a) these synthetic products will be generated to instruct regulatory T cells (Treg) to control inflammation and support tissue regeneration and, (b) to strengthen effector T cells to better combat cancer. One example are artificial immune receptors as novel biosensors (Bittner et al. PNAS, 2022). In this specific project, artificial sensors are developed to help regulatory T cells (Treg) better sense and more effectively fight inflammation. For this purpose, Treg cells are reprogrammed and equipped with new functions in order to develop completely new and innovative therapeutic concepts for the treatment of inflammatory diseases.

 

Publications (selected list)

  • Stüve P, Hehlgans T, Feuerer M. Alloreactive Tissue-resident Memory T Cells in Solid Organ Transplantation: Do They Light the Fire? Transplantation. 2022 Oct 1;106(10):1890-1891

  • 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)

  • Schmidleithner L, Feuerer M. Tfh cells induce intratumoral tertiary lymphoid structures. Trends Immunol. 2022 Apr;43(4):274-276

  • 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.

  • Delacher M, Barra MM, Herzig Y, Eichelbaum K, Mahmoud-Reza R, Richards DM, Träger U, Hofer AC, Kazakov A, Braband KL, Gonzalez M, Wöhrl L, Schambeck K, Imbusch, CD, Abramson J, Krijgsveld J, and Feuerer M.Quantitative proteomics identifies TCF1 as a negative regulator of Foxp3 expression in conventional T cells. iScience 2020 May 4;23(5):101127.

  • 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.

  • 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, FeuererM. Rjpj expression in regulatory T cells is critical for restraining TH2 responses. Nat Commun. 2019 Apr 8;10(1):1621

  • 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. Genome-wide DNA-methylation landscape defines specialization of regulatory T cells in tissues. Nature Immunology 2017 Oct;18(10):1160-1172

  • Herzig Y, Nevo S, Bornstein C, Brezis MR, Ben-Hur S, Shkedy A, Eisenberg-Bord M, Levi B, Delacher M, Goldfarb Y, David E, Weinberger L, Viukov S, Ben-Dor S, Giraud M, Hanna JH, Breiling A, Lyko F, Amit I, Feuerer M, Abramson J. Transcriptional programs that control expression of the Autoimmune regulator gene Aire. Nature Immunology. 2017;18(2):161-172.

  • Richards DM, Kyewski B, Feuerer M. Re-examining the nature and function of self-reactive T cells. Trends in Immunology. 2016;37(2):114-125.

  • Hettinger J, Richards DM, Hansson J, Barra BB, Joschko AC, Krijgsveld J and Feuerer M. Origin of monocytes and macrophages from a committed progenitor. Nature Immunology2013; 14(8):821-30.

  • Cipolletta D, Feuerer M, Li A, Kamei N, Lee J, Shoelson SE, Benoist C, Mathis D. PPAR-γ is a major driver of the accumulation and phenotype of adipose tissue Treg cells. Nature. 2012;486(7404):549-53.

  • Feuerer M, Hill JA, Kretschmer K, von Boehmer H, Mathis D, Benoist C. Genomic definition of multiple ex vivo regulatory T cell subphenotypes.PNAS 2010; 107(13):5919-24

  • Feuerer M, Shen Y, Littman D, Benoist C, Mathis D. How punctual ablation of Foxp3+ T cells unleashes an autoimmune lesion within the pancreas islets. Immunity 2009; 31(4):654-64.

  • 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. Nature Medicine 2009; 15(8):930-9.

  • Feuerer M, Hill JA, Mathis D, Benoist C. Foxp3+ regulatory T cells: differentiation, specification, subphenotypes. Nature Immunology 2009; 10(7):689-95.

  • Sundrud MS, Koralov SB, Feuerer M, Calado DP, Kozhaya AE, Rhule-Smith A, Lefebvre RE, Unutmaz D, Mazitschek R, Waldner H, Whitman M, Keller T, Rao A. Halofuginone inhibits TH17 cell differentiation by activating the amino acid starvation response. Science 324: 1334-8. 2009

  • Hill JA*, Feuerer M*, Tash K, Haxhinasto S, Perez J, Melamed R, Mathis D, Benoist C. Foxp3 transcription-factor-dependent and -independent regulation of the regulatory T cell transcriptional signature. Immunity 2007; 27 :786-800.
    *Equally contributed first author

  • Feuerer M, Jiang W, Holler PD, Satpathy A, Campbell C, Bogue M, Mathis D, Benoist C. Enhanced thymic selection of FoxP3+ regulatory T cells in the NOD mouse model of autoimmune diabetes. PNAS 2007; 104(46):18181-6.

  • Wu Y, Borde M, Heissmeyer V, Feuerer M, Lapan AD, Stroud JC, Bates DL, Guo L,Han A, Ziegler SF, Mathis D, Benoist C, Chen L, Rao A. FOXP3 controls regulatory T cell function through cooperation with NFAT. Cell 2006; 126, 375-87

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

  • 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. Nature Medicine2001; 7: 452-458.

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