CD83 expression is essential for Treg cell differentiation and stability
Marina Doebbeler, Christina Koenig, Lena Krzyzak, Christine Seitz, Andreas Wild, Thomas Ulas, Kevin Baßler, Dmitry Kopelyanskiy, Alina Butterhof, Christine Kuhnt, Simon Kreiser, Lena Stich, Elisabeth Zinser, Ilka Knippertz, Stefan Wirtz, Christin Riegel, Petra Hoffmann, Matthias Edinger, Lars Nitschke, Thomas Winkler, Joachim L. Schultze, Alexander Steinkasserer, Matthias Lechmann
Marina Doebbeler, Christina Koenig, Lena Krzyzak, Christine Seitz, Andreas Wild, Thomas Ulas, Kevin Baßler, Dmitry Kopelyanskiy, Alina Butterhof, Christine Kuhnt, Simon Kreiser, Lena Stich, Elisabeth Zinser, Ilka Knippertz, Stefan Wirtz, Christin Riegel, Petra Hoffmann, Matthias Edinger, Lars Nitschke, Thomas Winkler, Joachim L. Schultze, Alexander Steinkasserer, Matthias Lechmann
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Research Article Immunology

CD83 expression is essential for Treg cell differentiation and stability

Abstract

Foxp3-positive regulatory T cells (Tregs) are crucial for the maintenance of immune homeostasis and keep immune responses in check. Upon activation, Tregs are transferred into an effector state expressing transcripts essential for their suppressive activity, migration, and survival. However, it is not completely understood how different intrinsic and environmental factors control differentiation. Here, we present for the first time to our knowledge data suggesting that Treg-intrinsic expression of CD83 is essential for Treg differentiation upon activation. Interestingly, mice with Treg-intrinsic CD83 deficiency are characterized by a proinflammatory phenotype. Furthermore, the loss of CD83 expression by Tregs leads to the downregulation of Treg-specific differentiation markers and the induction of an inflammatory profile. In addition, Treg-specific conditional knockout mice showed aggravated autoimmunity and an impaired resolution of inflammation. Altogether, our results show that CD83 expression in Tregs is an essential factor for the development and function of effector Tregs upon activation. Since Tregs play a crucial role in the maintenance of immune tolerance and thus prevention of autoimmune disorders, our findings are also clinically relevant.

Authors

Marina Doebbeler, Christina Koenig, Lena Krzyzak, Christine Seitz, Andreas Wild, Thomas Ulas, Kevin Baßler, Dmitry Kopelyanskiy, Alina Butterhof, Christine Kuhnt, Simon Kreiser, Lena Stich, Elisabeth Zinser, Ilka Knippertz, Stefan Wirtz, Christin Riegel, Petra Hoffmann, Matthias Edinger, Lars Nitschke, Thomas Winkler, Joachim L. Schultze, Alexander Steinkasserer, Matthias Lechmann

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Figure 3

Expansion and suppressive capacity of CD83-deficient Tregs.

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Expansion and suppressive capacity of CD83-deficient Tregs. (A) Naive CD...
(A) Naive CD4+CD25+CD62L+ splenic Tregs were sorted and cultured with expansion beads and IL-2 and expansion rates were assessed after 10 days. (B) mRNA expression analyses revealed reduced GATA3 levels but increased IFN-γ. (C) Supernatants were collected at day 10 and expression of indicated cytokines was assessed. (D) Suppression assay: Treg cells were harvested at day 10 of expansion and WT cells from spleen were sorted for CD4+CD25– effector T cells. Cells were disseminated as triplets and cultured in R10 medium with feeder cells for 72 hours with or without stimulation with anti-CD3/CD28 alone or in mixed cultures. Triplets were pooled and proliferation was assessed using the CellTrace Violet Kit. (E) Transfer of isolated 0.3 × 106 CD4+CD25– WT or cKO effector T cells into RAG1−/− mice alone or together with 0.3 × 106 CD4+CD25+ WT or cKO Treg cells (1:1 ratio). The severity of transfer colitis symptoms was determined with the murine endoscopic score of colitis severity (n = 6; data presented are representative of 3 independent experiments). Graphs without asterisks are considered not significant.