Experimental Immunology

Every day we are attacked by a large number of different pathogens that our immune system tries to repel by using various strategies. To combat these, cells of the immune system have learnt to distinguish between harmless self structures and potentially dangerous foreign ones. Sometimes, however, immune cells are generated, which are falsely programmed and can attack structures in their own body. Learn more about the body`s protection against these cells and how we can use this mechanism in therapy.

1. Epigenetic control of immune cell development, differentiation and function

Although it is widely accepted that epigenetic mechanisms contribute to fixation of immune cell fates, molecular details are largely unknown. A better understanding of the events leading to engraved gene expression profiles will enable us to generate tailored immune cell subsets with epigenetically fixed functional properties for therapeutic purposes. In addition, only fragmentary knowledge has been accumulated about the impact of infections and environmental cues such as diet, commensal microbiota or chronic inflammation on immune cells’ epigenomes. These epigenetic modifications, particularly if acquired at young age, might have long-lasting and even life-long consequences for the functionality of the immune system. In three subprojects, we are investigating how epigenetic mechanisms contribute to immune cell development, differentiation and function.  

a) Epigenetic fixation of Foxp3 expression – get a lesson from the thymus

Regulatory T cells (Tregs) play an important role for the maintenance of self-tolerance and are characterized by the expression of the transcription factor Foxp3, which acts as a lineage-specification factor determining the suppressive function of these immunoregulatory cells. It has been demonstrated that Tregs require continuous expression of Foxp3 to ensure long-term stability of suppressive activity. Cells showing only instable Foxp3 expression rapidly loose their suppressive capacity. Thus, stability of Foxp3 expression is a critical issue for the therapeutic application of Tregs for the suppression of unwanted immune responses, including allotransplant rejections. Therefore, a better understanding of those mechanisms controlling stable Foxp3 expression is needed before adoptive Treg transfer therapies can be brought into the clinics.

We have previously demonstrated that stable Foxp3 expression is under epigenetic control, and that a CpG-rich evolutionarily conserved element within the Foxp3 locus, the TSDR (Treg-specific demethylated region), is selectively demethylated only in Foxp3+ Tregs displaying stable Foxp3 expression. We could recently show that the Foxp3 locus becomes progressively demethylated during maturation of thymic Tregs via an active mechanism that involves enzymes of the ten-eleven-translocation (TET) family causing hydroxylation of methylated cytosines. Currently, we are studying in detail which cellular players and molecular mediators contribute to the epigenetic fixation of the Treg fate within the thymus. This knowledge will be used to establish cell culture systems for the generation of stable, alloantigen-specific Foxp3+ Tregs for clinical applications.

This project is supported by the German Research Foundation (CRC738 “Optimization of conventional and innovative transplants”) (http://sfb738.de/project-c7.html)

b) Epigenetic signatures of murine and human T cell subsets

The differentiation of naïve conventional CD4+ T cells (Tconv) into highly specialized T helper cell subsets, such as Th1, Th2, Th17 and TFH cells, is accompanied by a number of epigenetic alterations, including global changes of the DNA methylation pattern, leading to the fixation of the unique effector cell phenotypes of the T helper cell subsets. By performing genome-wide methylome analyses of ex vivo isolated effector/memory T cell subsets, we could recently describe for the first time a Th17-specific epigenetic signature. Currently, we are analyzing corresponding signatures of human T helper cell subsets derived from healthy donors and allergic patients by performing whole-genome Bi‑seq.

This project is supported by the Helmholtz Association (Personalized Medicine Initiative “iMed”              (http://www.dkfz.de/en/imed/index.html) and the German Research Foundation (CRU250 “Genetic and cellular mechanisms of autoimmune diseases”) (KFO 250)

c) Microenvironmental factors imprint tolerogenic properties of stromal cells from gut-draining lymph nodes

3) Control of immunological synapse formation in regulatory T cells

4) Molecular targeting of Foxp3+ Tregs

Accumulating evidence suggests that tumor-bearing individuals and patients suffering from chronic infections harbor increased numbers of Foxp3+ Tregs, which prevent the development of efficient anti-tumor and pathogen-specific immune responses, respectively. Thus, the overall aim of this project is to develop novel therapeutic strategies that selectively modulate the suppressive activity of Foxp3+ Tregs in order to unleash preexisting anti-tumor or pathogen-specific immunity or to enhance the efficacy of antigen-specific vaccinations. This project is based on a selection of promising natural compounds derived from myxobacteria that were recently identified in a screening approach to inhibit Foxp3 expression in ex vivo isolated Tregs and to prevent de novo induction of Foxp3 in TGF‑b-induced Tregs. We will use primary T cells from mice and men to study the effect of the candidate compounds on the Tregs’ suppressive capacity to unravel their mode-of-action and to rule out any undesired effects on differentiation and function of effector T cells. Furthermore, we will investigate the efficacy of the in vivo therapeutic administration of the candidate compounds in pre-clinical disease and vaccination models.

This project is supported by the Wilhelm-Sander Foundation (http://www.sanst.de).

Leader

  • Prof Jochen Hühn

    Jochen Hühn

    Head of Department

    +49 531 6181-3310

    +49 531 6181-3399

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