Background: Autoimmune inflammation creates a niche in the CNS that persists even after resolution of inflammation. This niche is prominently populated with Foxp3+ Treg cells, which we term rec CNS Treg cells.
Hypothesis: We hypothesize that rec CNS Treg cells have unique phenotypic and functional properties both in terms of their immune functions and in terms of their interaction with CNS-intrinsic cells, which may be controlled by the transcription factor Blimp1 as a specific transcriptional checkpoint.
Strategy: We will use advanced genetic loss-of-function approaches and advanced transcriptome analysis techniques in order to assess the role of Blimp1 in rec CNS Treg cells in the postinflammatory CNS.
The role of Foxp3+ Treg cells in maintaining immune homeostasis is well established. However, some Foxp3+ Treg cells reside in non-lymphoid tissues including adipose tissue, the skin, and the CNS. Recently, Treg cell functions in non-lymphoid tissues have been identified that are not connected to their capacity to regulate inflammation. For example, in the skin, Treg cells have been shown to control the function of hair follicles and in the visceral adipose tissue (VAT), they control the insulin sensitivity of adipocytes . These functions of Foxp3+ Treg cells may be termed "non-canonical" since they are not directly related to immune regulation. We have found that the expression of the transcription factor Blimp1 in CNS Treg cells is a non-redundant checkpoint for the maintenance of Foxp3 expression in the CNS during inflammation. By suppressing a distinct methyltransferase, Blimp1 prevents the Foxp3 locus from becoming methylated and transcriptionally inactive. Thus, high expression of Blimp1 is required to maintain Foxp3 expression and preserve the "identity" of Treg cells in the CNS. Moreover, in the context of tissue resident memory CD8+ T cells, Blimp1 has also been described to control a transcriptional programme in T cells that establishes their tissue residency (e. g. by downregulation of sphingosine-1-phosphate receptor). Here, using a system of induced Treg cell-conditional ablation of Prdm1 (which encodes Blimp1), we will test the role of Blimp1 in Treg cells as a checkpoint for tissue residency of CNS Treg cells and as a checkpoint for canonical (i. e. immune regulatory) and "non-canonical" functions of CNS Treg cells after resolution of inflammation. In exploring non-canonical functions of CNS Treg cells, we will particularly focus on the potential interaction of Treg cells with astrocytes, characterize it morphologically and functionally for its impact on astrogliosis and metabolic fitness of astrocytes.
