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PTEN in antigen presenting cells is a master regulator for Th17-mediated autoimmune pathology

Autoreactive T cells are a central element in many systemic autoimmune diseases. The generation of these pathogenic T cells is instructed by antigen presenting cells. However, signalling pathways in APC that drive autoimmunity are not completely understood. Here we show that that conditional deletion of PTEN in myeloid cells are almost completely protected from the development of two prototypic model autoimmune diseases, collagen induced arthritis (CIA) and experimental autoimmune encephalomyelitis (EAE). Myeloid specific deletion of PTEN lead to a significant reduction of cytokines pivotal for the induction of systemic autoimmunity such as IL-23 and IL-6 in vitro and in vivo. In addition, PTEN deficient dendritic cells showed reduced activation of p38 MAP-kinase and increased inhibitory phosphorylation of GSK3β in vitro. Dendritic cell and macrophage phenotypic maturation and migration to lymph nodes as well as collagen specific T and B cell activation was comparable in wt and myeloid specific PTEN-/-. However, analysing the impact of myeloid specific PTEN deficiency on T cell polarization, we found a significant reduction of a Th17 type of immune response characterized by reduced production of IL-17 and IL-22. Moreover, there was an increase in IL-4 production and higher numbers of regulatory T cells myeloid specific PTEN-/-. In contrast, myeloid specific PTEN deficiency did not affect serum transfer arthritis, which is independent of the adaptive immune system and solely depends on innate effector functions. These data demonstrate that the presence of PTEN in myeloid cells is required for the development of systemic autoimmunity. Deletion of PTEN in myeloid cells inhibits the development of CIA and EAE by preventing the generation of a pathogenic Th17 type of immune response.

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Correspondence to Stephan Blüml or Gernot Schabbauer.

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Keywords

  • Dendritic Cell
  • Experimental Autoimmune Encephalomyelitis
  • Antigen Present Cell
  • Myeloid Cell
  • Adaptive Immune System