Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
Walter, J.
Succinate sensing via GPR91 modulates CD4+ T cell functionality.
[ Diplomarbeit/Master Thesis (UNI) ] TU Graz; 2022. pp.73.
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- Autor*innen der Med Uni Graz:
- Betreuer*innen:
- Angiari Stefano
- Strobl Herbert
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- Abstract:
- The Krebs cycle intermediate succinate accumulates in peripheral tissues during inflammatory responses, and local tissue cells as well as infiltrating immune cells can sense its presence through the succinate receptor GPR91 (succinate receptor 1, SUCNR1). In particular, high succinate concentrations have been detected in the tumor microenvironment, where it promotes cancer growth and metastasis by affecting both tumor and immune cell functionality. Several immune cells can sense succinate via GPR91, but the effect of succinate on T lymphocytes is currently unknown. Preliminary data from our group indicated that murine CD4+ T cells express GPR91, and that extracellular succinate influences cytokine production by murine T cells. In this project, we analyzed GPR91 expression on human CD4+ T cells and investigated the impact of succinate on their polarization towards different T helper cell subsets. We first confirmed that human naïve CD4+ T cells isolated from peripheral blood express GPR91 on their surface. Additional experiments also suggested that GPR91 expression is modulated by T cell activation, and that different T helper cell subsets are potentially able to sense extracellular succinate. We also detected GPR91 on T cells in murine spleen and lung tumors, confirming that T cells may sense succinate in vivo. When analyzing the effect of succinate on T cell polarization, we observed that succinate does not influence the overall polarization of the different T cell subsets. However, we found that succinate increases the production of interleukin-5 (IL-5) in vitro by TH2 and TH1 cells, but not by TH17 and TReg cells. Finally, we demonstrated that succinate boosts IL-5 production by TH2 cells in a GPR91-dependent manner. Overall, our data support the hypothesis that T cells can sense extracellular succinate, and that succinate affects T cell functionality via interaction with GPR91. Given the important role of IL-5 in inflammatory responses, such as in the tumor microenvironment and during allergic and atopic diseases, our results point at GPR91 as a potential target to modulate T cellmediated inflammation in such pathologies.