1 PhD project offered in the IPP winter call 2020/2021
Regulatory T cells (Treg cells) can be considered as the most important negative regulators of the immune system, balancing overshooting immune responses and preventing autoimmunity. Stability and function of Treg cells depends on continuous expression of the transcription factor Foxp3, which is controlled by epigenetic regulation as well as posttranslational modifications. The foxp3 gene locus comprises 12 exons and four conserved non-coding sequence (CNS0 to CNS3) regions, which are located in introns near the promoter. Epigenetic modification of the Foxp3 gene was identified as the most reliant marker for stable expression: Demethylation of the Foxp3 promoter and highly conserved CpG islands in the CNS2 region, termed Treg cell-specific demethylated region (TSDR), were defined as a prerequisite for stable Tregs cells. In addition, Foxp3 gene transcription is regulated by histone modifications, in particular acetylation and methylation.
PhD project proposal: The role of cAMP for regulatory T cell homeostasis and function
The exact mechanisms how regulatory T cells (Treg cells) suppress are still an area of intense research. Elevated levels of cyclic adenosine monophosphate (cAMP) are considered to be essential for many suppressive effects on effector T cells (Teff cells) and antigen presenting cells (APC). We could demonstrate that Phosphodiesterase 3B (PDE3B), an enzyme degrading cAMP and a known target of FoxP3, is highly upregulated in non-functional Treg cells from scurfy mice leading to reduced cAMP levels and a loss of suppressive function. In addition, we identified a Treg cell-specific miRNA cluster targeting Pde3b in mice and humans implying PDE3B as an important regulator of Treg cell function. cAMP acts via a potent transcriptional inhibitor, inducible cAMP early repressor (ICER), a molecule also highly expressed by Treg cells. To specifically address the role of cAMP for the suppressive function of Treg cells we plan to study the importance of this pathway using tissue-specific conditional knock-out mice. We would like to understand the in vivo function of this pathway for regulating inflammatory diseases such as colitis and experimental autoimmune encephalitis and dissect the links between mitochondrial metabolism and anti-inflammatory immunity..
Publications relevant to the project:
Pace, L., Tempez, A., Arnold-Schrauf, C., Lemaitre, F., Bousso, P., Fetler, L., Sparwasser, T., and Amigorena, S. (2012). Regulatory T cells increase the avidity of primary CD8+ T cell responses and promote memory. Science 338, 532-536.
Ohkura, N., …, T. Sparwasser, K. Nakai, and S. Sakaguchi. (2012). T cell receptor stimulation-induced epigenetic changes and Foxp3 expression are independent and complementary events required for Treg cell development. Immunity 37:785-799.
Vaeth, M., Gogishvili, T., Bopp, T., Klein, M., Berberich-Siebelt, F., Gattenloehner, S., Avots, A., Sparwasser, T., Grebe, N., Schmitt, E., Hunig, T., Serfling, E., and Bodor, J. (2011). Regulatory T cells facilitate the nuclear accumulation of inducible cAMP early repressor (ICER) and suppress nuclear factor of activated T cell c1 (NFATc1). Proc Natl Acad Sci U S A 108, 2480-2485.
Lahl, K., Mayer, C.T., Bopp, T., Huehn, J., Loddenkemper, C., Eberl, G., Wirnsberger, G., Dornmair, K., Geffers, R., Schmitt, E., Buer, J., and Sparwasser, T. (2009). Nonfunctional regulatory T cells and defective control of Th2 cytokine production in natural scurfy mutant mice. J Immunol 183, 5662-5672.
Lahl, K., Loddenkemper, C., Drouin, C., Freyer, J., Arnason, J., Eberl, G., Hamann, A., Wagner, H., Huehn, J., and Sparwasser, T. (2007). Selective depletion of Foxp3+ regulatory T cells induces a scurfy-like disease. J Exp Med 204, 57-63..