The role of the transcription factor c-Maf in controlling mucosal inflammation in the intestine
Immunology
Final Report Abstract
Chronic inflammatory diseases (CID), such as inflammatory bowel diseases, are steadily rising in industrialized countries. They are mediated via dysregulated immune reaction in the intestine, most likely targeting harmless intestinal microbiota. Current treatment options are not curative but rely on broad immune suppression. The immune system has evolved mechanisms to tolerate harmless microbiota securing peaceful coexistence. These include specialized populations of immune suppressive T cells, so called regulatory T cells (Tregs), and anti-inflammatory mediators, such as Interkeukin-10 (IL-10), a potent anti-inflammatory substance which can be produced by various immune cells, including Tregs. How these anti-inflammatory functions of the immune system are regulated and how defects contribute to CIDs is a key question of immunological research. Their targeted modulation represents an attractive therapeutic opportunity aiming at utilization of these physiological processes and potentially re-establishing the natural balance and induce stable remission. We followed the hypothesis that c-Maf, a transcription factor expressed in various immune cell types, such as T cell subsets or macrophages may represent a key regulator for intestinal tolerance including the regulation of IL-10 production and potentially other effector molecules. We showed in murine models that c-Maf in is particularly expressed in an intestinal subset of RORgT+ Tregs specialized on immune suppression and tolerance. A loss of c-Maf specifically in Tregs resulted in a loss of this Treg population as well as in a loss of IL-10 production by Tregs. This led to an increased production of so called Th17 cytokines (IL-17/IL-22). Surprisingly the increased Th17 responses resulted in protection from experimentally induced colitis, supporting the idea that Th17 has a protective rather than a pathogenic role in gut inflammation. This confirmed our hypothesis that c-Maf in Treg plays an important role in the regulation of the immune response in the intestine. We also analyzed IL-10 regulation in human T cells and developed a new IL-10 inducing protocol, involving co-signaling of STAT3 activating cytokines with Notch signals. IL-10 production was strictly dependent on c-Maf and Blimp-1. We showed that all T helper cell subsets, including proinflammatory Th1 and Th17 cells, can transiently produce IL-10, identifying a self control mechanism of inflammatory T cells. This induction mechanism was defective in patients with Crohns Disease. Overall we demonstrate a critical role of c-Maf for Treg subset differentiation in the intestine as well as for IL-10 production in human and murine T cells which are both of central importance for the maintenance of tolerance. In the future we will further focus on the regulation of IL-10 in human T cells, including Tregs with the aim to translate this information into clinical applications.
Publications
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c-Maf-dependent Treg cell control of intestinal TH17 cells and IgA establishes host–microbiota homeostasis. Nature Immunology, 20(4), 471-481.
Neumann, Christian; Blume, Jonas; Roy, Urmi; Teh, Peggy P.; Vasanthakumar, Ajithkumar; Beller, Alexander; Liao, Yang; Heinrich, Frederik; Arenzana, Teresita L.; Hackney, Jason A.; Eidenschenk, Celine; Gálvez, Eric J. C.; Stehle, Christina; Heinz, Gitta A.; Maschmeyer, Patrick; Sidwell, Tom; Hu, Yifang; Amsen, Derk; Romagnani, Chiara; ... & Scheffold, Alexander
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Functions and regulation of T cell-derived interleukin-10. Seminars in Immunology, 44, 101344.
Neumann, Christian; Scheffold, Alexander & Rutz, Sascha
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A Notch/STAT3-driven Blimp-1/c-Maf-dependent molecular switch induces IL-10 expression in human CD4+ T cells and is defective in Crohn´s disease patients. Mucosal Immunology, 15(3), 480-490.
Ahlers, Jonas; Mantei, Andrej; Lozza, Laura; Stäber, Manuela; Heinrich, Frederik; Bacher, Petra; Hohnstein, Thordis; Menzel, Lutz; Yüz, Simge G.; Alvarez-Simon, Daniel; Bickenbach, Anne Rieke; Weidinger, Carl; Mockel-Tenbrinck, Nadine; Kühl, Anja A.; Siegmund, Britta; Maul, Jochen; Neumann, Christian & Scheffold, Alexander
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The role of A Disintegrin and Metalloproteinase (ADAM)-10 in T helper cell biology. Biochimica et Biophysica Acta (BBA) - Molecular Cell Research, 1869(4), 119192.
Sezin, Tanya; Selvakumar, Balachandar & Scheffold, Alexander
