Regulatory T cells in CNS injury: the simple, the complex and the confused

Abstract

Regulatory CD4(+)CD25(+)Foxp3(+) T cells (Tregs) have been the focus of significant attention for their role in controlling immune responses. Although knowledge of Treg biology has burgeoned, wide gaps remain in our understanding of Treg function under both normal and pathological conditions. Pioneering studies demonstrated roles for Tregs in cancer and autoimmune diseases, including experimental autoimmune encephalitis, and this knowledge is often applied to other pathologies including neurodegenerative conditions. However, differences between immunity in neurodegeneration and in malignancy or autoimmunity are often neglected. Thus, Treg manipulations in central nervous system (CNS) neurodegenerative conditions often yield unexpected outcomes. In this piece, we explore how the immunology of neurodegeneration differs from that of cancer and autoimmunity and how these differences create confusion about the role of Tregs in neurodegenerative conditions.

Figure 1. Model of proposed Treg-based therapeutic interventions in different pathological conditions

While the role of Treg is well studied in cancer and autoimmune diseases (green shaded areas), its role in CNS acute and chronic neurodegenerative conditions (grey shaded) is understudied. In autoimmune diseases, including experimental autoimmune encephalomyelitis (EAE), increasing suppression of Tregs would ameliorate symptoms of the disease, whereas inhibiting the Treg suppression would be the therapeutic aim in cancer. We propose that in acute CNS injury Treg suppression needs to be inhibited immediately after injury to allow a beneficial autoimmune response, but then in the late stage of injury this suppression needs to be reinstated to prevent destructive autoimmune attack from developing.