Macroautophagy in dendritic cells (DCs) controls the stability of the regulatory T cell compartment and the severity of arthritis

Macroautophagy in dendritic cells (DCs) controls the stability of the regulatory T cell compartment and the severity of arthritis

Jennifer Niven, Natacha Madelon, Nicolas Page, Assunta Caruso, Sylvain Lemeille, Christian Seemayer, Stéphanie Hugues and Monique Gannagé*

Regulatory T cells (Tregs) play a crucial role in controlling autoimmune and inflammatory responses. The molecular signature of Tregs is the expression of the transcriptional factor Foxp3 that is essential for their function and homeostasis. Peripheral Tregs from mice lacking autophagy in their DCs (Atg5 ^flox/flox CD11c-Cre+ mice), are enriched in the CD25^low subset of unstable Tregs that have been described to lose Foxp3 expression in the context of inflammation. RNA sequencing data have confirmed a signature of unstable Tregs in these mice. We analyzed Tregs/ DCs interaction and demonstrated that deletion of autophagy in dendritic cells results in reduced DC/Tregs conjugates as well as reduced priming of polyclonal and antigen induced Tregs. The precise molecular mechanism behind this phenotype is linked to a reduced expression of ICOS-Ligand in autophagy deficient Dcs. As a consequence in two models of autoimmune and inflammatory arthritis, collagen induced arthritis and antigen induced arthritis, the disease is more severe in Atg5^flox/flox CD11c-Cre+ mice. By adoptively transferring Tregs during arthritis we demonstrated their conversion towards Th17 in Atg5^flox/flox CD11c-Cre+ mice. Our data has revealed a new mechanism that couples autophagy in DCs to the stability of peripheral Tregs.

Key idea/result:

Since genome wide association studies have linked autophagy gene polymorphisms to autoimmune diseases including lupus and rheumatoid arthritis (RA), we propose that autophagy dysfunction in the context of autoimmune disorders could result in Tregs instability.

Author:

Jennifer Niven is a senior post-doctoral scientist at the University of Geneva. Her major scientific interest is the contribution of autophagy to the adaptive immune response during RA.

Link to publication This manuscript is in the final process of revision prior to publication

Key words:

• Autophagy
• Arthritis
• Regulatory T cells
• ICOS-Ligand