Examining the role of transcription factor c-maf in regulatory T cell differentiation and function in tumor tolerance and immune evasion

• Applicant: Dr. Jonas Blume
• Subject Area: Immunology
• Term: from 2017 to 2020
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 348288595

Regulatory T cells (Tregs) represent a subset of thymus derived lymphocytes (T cells) with immune suppressive capacities. They are critically important throughout the whole life in mice and humans, since deficiencies or malfunctions cause spontaneous development of systemic autoimmunity. Treg development and function is driven by the pivotal transcription factor Foxp3, functional T-cell receptor (TCR) signaling and presence of the cytokine IL-2. Recently, it has been established that homeostasis and function of highly active, tissue resident Tregs (termed effector Tregs) relies on additional environmental factors (cytokines, soluble factors) and a broad network of transcription factors (IRF4, T-bet, Rorgt, Gata3 and Bcl6) resembling helper T cell differentiation. This allows eTregs to survive in the milieu of non-lymphoid tissues, which can be deprived of IL-2 in a non-inflammatory state.  The transcription factor c-maf was proposed to be involved in regulation of effector molecules in T cells, its expression being regulated by cytokines along TCR co-stimulation. Due to embryonically lethality of c-maf deficiency, most functional evidences are indirect and detailed studies are currently lacking. Noteworthy, there are to date no publications addressing the role of c-maf in Tregs.  Yet, preliminary data and gene expression data show that c-maf is highly expressed in activated Tregs especially from non-lymphoid tissues. c-maf interacts with factors critical for eTreg function (IRF4, Bach2). Therefore, we hypothesise that c-maf is relevant for the differentiation or function of eTregs.  Utilizing mouse models with a Treg specific deletion of c-maf, this project aims to carefully examine its role in eTreg differentiation and function. Potentially altered Treg function will be addressed in classical assays but will also be assessed in the context of tumor immunology. Developing tumors frequently employ the immune suppressive mechanisms of Tregs to escape an efficient T cell mediated immune response. Hence, highly-active tumor derived Tregs are an ideal representative for eTregs and represent a focus of ongoing research in cancer-immunology. Deeper understanding of their function in tumor development will be crucial to develop new therapeutic strategies for patient care. This project aims to uncover the role of c-maf in Tregs and its role in eTreg differentiation and function. It furthermore proposes to deepen the understanding of eTregs in the context of tumor immune evasion with an emphasis on c-maf function. The knowledge generated in this project might help to develop new therapeutic strategies in cancer treatments. 

• DFG Programme: Research Fellowships
• International Connection: Australia
• Host: Dr. Axel Kallies