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03.17 Impaired mitophagy in tregs is involved in breakdown of self-tolerance and development of autoimmune responses
  1. Maria Lazari,
  2. Lydia Kalafati,
  3. Themis Alissafi,
  4. Panayotis Verginis
  1. Biomedical Research Foundation Academy of Athens, Athens, Greece

Abstract

Background Regulatory T cells (Tregs) play a major role in the maintenance of immune homeostasis and in the suppression of autoimmune responses. Breakdown of immune tolerance, a hallmark of autoimmune diseases, has been linked to both altered generation and impaired function of Tregs. However, the mechanism that leads to this defect remains elusive. Mitochondria are indispensible for proper function of the cell and clearance of damaged mitochondria through operation of mitophagy is essential for the survival of the cell. However whether this mechanism is functional in Tregs during an autoimmune response has not been demonstrated. Thus our hypothesis is that impaired mitophagy in Tregs could affect their suppressive capacity and lead to development of autoimmune disorders.

Materials and methods For the purposes of this study, we utilised Foxp3gfp.KI transgenic mice that express the gfp protein under the promoter of the foxp3 gene and Atg5ΔCd4 mice, which lack the autophagy pathway in CD4+ T cells. Experimental Autoimmune Encephalomyelitis (EAE) was induced by immunisation with the myelin peptide (Mog35-55) emulsified in complete Freund adjuvant (CFA).

Results Herein we show that Tregs isolated from draining lymph nodes of Mog35-55/CFA immunised mice exerted increased autophagosome formation and lysosomal function compared to naïve Tregs, whereas their mitophagy was impaired. In addition Tregs from immunised animals exhibited decreased mitochondrial membrane potential, enhanced production of mitochondrial ROS and increased metabolic requirements compared to naïve mice. Finally, Tregs deficient in authophagy demonstrated elevated numbers of mitochondria, increased production of mitochondrial ROS and lysosomal function.

Conclusions Overall, our results indicate an impaired mitophagy in Tregs during an autoimmune response that results in accumulation of dysfunctional mitochondria that might contribute to loss of Treg suppressive function. Future experiments will be focused on understanding the molecular mechanism underlying the deregulated mitophagy in Tregs in autoimmune disorders that will orientate us in new potential therapeutic targets.

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