Autophagy-dependent TIGIT+ Treg are critical for the maintenance of tolerance

Abstract Regulatory T cells (Treg) play a crucial role in the maintenance of peripheral tolerance. Quantitative and/or qualitative defects in Treg result in diseases such as autoimmunity and graft-versus-host disease (GVHD), a serious complication of bone marrow transplantation (BMT). We recently reported that G-CSF mobilisation of stem cells in donor mice increases autophagy related genes in Treg and it is associated with an improved GVHD outcome after BMT. Autophagy is a self-degradative process for cytosolic components which promotes cell homeostasis and survival. Here, we demonstrate that the lineage-specific disruption of autophagy within FoxP3+ Treg (Atg7fl/fl.FoxP3cre+ mice) resulted in a profound loss of Treg within the bone marrow (BM). This resulted in dysregulated effector T cell activation and expansion, and in aged mice, the development of enterocolitis and severe scleroderma. We show that the BM compartment is highly enriched in TIGIT+ Treg and that this subset is differentially lost in the absence of autophagy. Moreover, G-CSF administration to naive mice results in the mobilization of BM TIGIT+ Treg explaining the autophagy signature of peripheral Treg in G-CSF treated mice. Importantly, lethally irradiated B6D2F1 recipients of splenic grafts from G-CSF mobilized B6.Atg7fl/fl.FoxP3cre+ donors failed to reconstitute the Treg compartment within the BM. This resulted in GVHD exacerbation and reduced survival compared to recipients of B6.WT.FoxP3cre+ grafts. Collectively, these data indicate that autophagy-dependent TIGIT+ Treg in the BM are critical for the maintenance of tolerance and to control GVHD; thus the induction of autophagy may represent an attractive immune-restorative therapeutic strategy.