Interferons in Treg development and function

Abstract

Abstract Thymus-derived regulatory T-cells (Tregs) are critical for controlling immune responses and preventing autoimmunity. In the setting of viral infection, Tregs are important modulators of anti-viral immune responses and help resolve inflammation. The subset of Tregs responsible for responding to viral infections and the types of antigens they recognize are not well understood. Using single-cell RNA sequencing we identified a unique subset of thymic Treg progenitors and mature Tregs that express a strong interferon stimulated gene (ISG) signature, as well as a comparable population in the spleen. Importantly, the ISG signature is much stronger than that expressed by thymocytes receiving tonic IFN stimulation in the final stages of maturation prior to thymic egress. Using flow cytometry we established that APCs in the thymus, including mTECs, as well as SIRPα+ and CD8α+ dendritic cells, require IFNα/β or IFNλ, acting via STAT1 signaling, for the expression of the canonical ISG BST2. TCR specificity was important for selection into this subset as SM1 TCR transgenic mice, which express a TCR that recognizes a non-ISG encoded antigen, have a reduced compartment of ISG-expressing CD4SP T-cells in the thymus. We are currently generating mice that specifically lack the ISG-signature Treg subset to test their function in vivo. Based on our current findings, we propose that thymic ISG antigens serve as TCR ligands for inducing the differentiation of ISG-signature Tregs that are in close physical proximity to the ISG-producing APCs. Furthermore, we hypothesize that ISG-signature Tregs are specialized for responding to ISGs induced during antiviral immune responses and play a key role in controlling IFN-driven inflammation.