Blimp-1 transcriptional repressor controls the TH17 cell metabolic remodelling

• Applicant: Theodora Agalioti, Ph.D.
• Subject Area: Immunology
• Term: since 2022
• Project identifier: Deutsche Forschungsgemeinschaft (DFG) - Project number 499179547

CD4+ TH17 cells underlie autoimmune diseases such as Multiple Sclerosis (MS) and Inflammatory Bowel disease (IBD) and have important roles in homeostasis and inflammation. How TH17 cells balance their pathogenic and regulatory functions is not understood. Upon TCR engagement/co-stimulation and under IL-2/IL-2R signaling, the CD4+ TH17 cells, undergo proliferation, a phase which is followed by their profound metabolic remodeling downstream of IL-23/IL-23R axis. During metabolic remodeling TH17 cells acquire their full effector and pathogenic functions. Later on, during the resolution of immune response, TH17 cells convert into anti-inflammatory regulatory TR1 cells. The mechanisms by which TH17 cell metabolic remodeling is taking place are beginning to emerge, however how these processes are controlled is currently unknown. Current notion postulates that the cell metabolism is post-transcriptionally regulated. Nevertheless, whether the metabolic switch to pathogenic TH17 cells is controlled by a single transcription factor, is an open question. If such a “gatekeeper” of TH17 cell pathogenicity indeed exists, it would portend immense therapeutic potential for autoimmunity. The role of Prdm1/Blimp1 transcriptional repressor in TH17 cells is currently controversial. This is because, depending on whether Prdm1 floxed gene is deleted via the CD4Cre, proximal LckCre or the distal LckCre drivers, Blimp1 has been assigned both pro-and anti-inflammatory roles in CD4+ TH17 cells. To resolve this conundrum, we have conditionally deleted Prdm1 in TH17 via the Il17aCre driver. We found that the Blimp1 deficient TH17 cells from Il17aCrePrdm1fl/fl animals proliferate more but they do not mature to full effector T cells. We hypothesize that during inflammation and as a terminal differentiation factor, Blimp1 globally regulates the TH17 cell proliferation, maturation and anti-inflammatory capacities, by gradually shaping the TH17 cell epigenome. This gradual process largely depends on the Blimp1 -incrementally rising- intracellular concentrations, under the auspices of the IL-2/IL2R, IL-23/IL-23R and IL-27/IL27R signaling axes. We provide further evidence that downstream of IL-23/IL23R axis, Blimp1 upregulates the transcription of key genes, which in turn, control glutaminolysis and the aminopurine metabolism, two biochemical pathways promoting the TH17 metabolic remodeling. We propose to examine this hypothesis, by using the Experimental Autoimmune Encephalitis (EAE) mouse model in combination with genetic and epigenetic techniques. We aim to shed light into the principles controlling the TH17 cell pathogenicity in immune mediated diseases and identify new potential therapeutic targets.

• DFG Programme: Research Grants