Empowering Regulatory T Cells in Autoimmunity

Abstract

Regulatory T cells (Tregs) are capable of dampening immune-mediated inflammation and avert the destructive effects of uncontrolled inflammation. Distinct molecules and pathways, including various transcription factors, phosphatases, and kinases, impact the ability of Tregs to function as negative regulators of the immune response, and are presumably amenable to therapeutic manipulation. Here, we discuss recently identified molecular networks and the therapeutic potential for treating autoimmune diseases.

Figure 1. Treg-specific Pathways Affecting Foxp3 Expression

Murine studies have revealed that TCR and IL-2 lead to NFAT and STAT5b binding to the CNS2 locus, stabilizing Foxp3 expression. TCR engagement and IL-2 trigger PI3K-Akt-mTOR signaling which is negatively regulated by PTEN. Negative regulation of the PI3K-Akt-mTOR axis stabilizes Foxp3 expression. Nrp-1-SEMA4a inhibits PI3K and promotes PTEN, stabilizing Foxp3 expression. Depicted are two pathways of Notch signaling; the non-canonical promotes mTORC2 signaling tagging FOXO1 preventing nuclear translocation thereby destabilizing Foxp3 expression; the canonical pathway facilitates NF-κB nuclear translocation resulting in cellular proliferation.

Figure 2. _[A2]PP2A Is Required for Treg Function

(1) Foxp3 inhibits sgms1; (2) SMS1 protein is not produced, therefore ceramide is not degraded, accumulating in the cytoplasm; (3) SET is upregulated upon T cell activation and ceramide binds SET, making it less available to inhibit PP2A. (4) PP2A is activated when unbound from SET (5) Active PP2A inhibits mTORC1 activity, thereby promoting Foxp3 expression.