Funktionelle Analyse des Immunmodulators sCD83 bei der Pathogenese und Therapie von chronisch entzündlichen Darmerkrankungen
Zusammenfassung der Projektergebnisse
Inflammatory bowel diseases (IBD) are still a major threat for many patients worldwide and improvement of therapies is urgent. The overall long term aim of this project is the development of an efficient new strategy, with low side effects, for the therapy of patients with autoimmune disease as IBD. Several publications by us and other groups could already show that the CD83 molecule is important for immune homeostasis and T cell development and that soluble CD83 has a great therapeutic potential for the therapy of autoimmune disorders such as inflammatory bowel diseases. New therapeutic approaches target Treg cells to induce tolerance. But, one major obstacle in Treg cell-based therapy is the loss of adoptively transferred Tregs or iTregs over-time in the patients. It is not completely understood how different intrinsic and environmental factors control Treg differentiation. Interestingly, CD4+CD25+Foxp3+ Tregs rapidly and strongly induce the transcription of CD83 after activation. Using CD83eGFP reporter mice, we recently reported that CD83 protein expression is correlated to murine T cells that have highly upregulated Treg-associated molecules. Additionally, human Tregs were also found to express CD83 at the mRNA level as well as at the protein level. But, the precise functional relevance and the implication of endogenous CD83 expression specifically in regulatory T cells was still obscure. Better knowledge of crucial factors regulating survival, stability of the individual suppressive functions and Treg plasticity is mandatory for the development of new and more efficient treatment strategies. Thus, within this proposed project and based on our previous data we focused on the modulation of Treg stability and plasticity by CD83. Complete CD83 cKO mice lack normal peripheral CD4+ T cell populations. Thus, for functional studies regarding CD83 effects on Tregs, we generated specific CD83 conditional knockout animals, whereby CD83 expression has only been deleted in Foxp3+ Tregs. Very interestingly, Treg specific CD83 deficiency in mice shifts the immune system towards a pro-inflammatory profile, aggravated autoimmunity and an impaired resolution of inflammation. Thus, adaptive transfer of total CD4+ T cells from CD83cKO mice revealed an increased mortality and augmented colitis symptoms. Strikingly, the loss of CD83 expression by Tregs alone leaded to the downregulation of Treg-specific differentiation markers and the induction of an inflammatory profile. We also found that CD83 is essential for Treg cell stability and late differentiation upon activation. We found that the CD83-TLR axis and regulation of factors as IRAK1, NFATc2 and GATA3 play important roles in the observed Treg modulation. However, these signaling pathways have to be investigated in more detail in future studies. Since Treg cells play a crucial role in the maintenance of immune tolerance and thus prevention of autoimmune disorders our findings are clinically highly relevant as we provide a new striking potent pathway to modulate T cell tolerance. Since we earlier demonstrated that CD83 expression in human Tregs is also rapidly and strongly enhanced upon activation, similar functions in human Treg differentiation is very likely. Finally, our results showing a new role of CD83 expression in Treg cell plasticity may help find new pathways and therapeutic intervention strategies to specifically modulate Treg differentiation upon activation and memory development for the therapy of autoimmune disorders such as inflammatory bowel diseases. Regarding sCD83 treatment of IBD we revealed that sCD83 protected mice from DSS colitis symptoms and improved the recovery. The treatment of the DSS challenged mice with sCD83 improved weight gain and slightly reduced the endoscopic score. In addition sCD83 treated animals showed enhanced expression of tolerogenic factors as IDO1, Foxp3 and IL-10 together with clearly elevated levels of cytokines as IL-22 and IL-17A promoting the epithelial cell proliferation phase and recovery of the protective mucosal barrier by goblet cell restitution. Thus, our data are the first indication that CD83 is also involved in stabilization and regeneration of the intestinal barrier.
Projektbezogene Publikationen (Auswahl)
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CD83 expression is essential for Treg cell differentiation and stability. JCI Insight. 2018 Jun 7:3(11). pii: 99712
Doebbeler M, Koenig C, Krzyzak L, Seitz C, Wild A, Ulas T, Baßler K, Kopelyanskiy D, Butterhof A, Kuhnt C, Kreiser S, Stich L, Zinser E, Knippertz I, Wirtz S, Riegel C, Hoffmann P, Edinger M, Nitschke L, Winkler T, Schultze JL, Steinkasserer A, Lechmann M
