The glycoprotein F4/80 (brown) is required for the induction of CD8+ T reg cells that prevent immune attack on the eye.

On page 1615, Lin and colleagues show that an adhesive glycoprotein is essential to prevent the immune system from reacting to environmental antigens encountered by the eyes. The authors show that this glycoprotein, known as F4/80, induces CD8+ regulatory T (T reg) cells thus protecting the eye and perhaps other immune-privileged sites from immune attack.

The F4/80 glycoprotein was first described over two decades ago and has since served as a sensitive marker of resident tissue macrophages. However, this protein had no identified function or ligand. Previous studies by this group showed that F4/80+ antigen presenting cells (APCs) carry antigens from the eye to the spleen. Once there, the APCs induce the development of CD8+ T reg cells, which in turn inhibit the activation of pathogenic CD4+ T cells and B cells.Lin et al. now show a direct role for the F4/80 protein in tolerance induction, as mice lacking this protein fail to generate CD8+ T reg cells after ocular antigen challenge. Although the mechanism is unknown, the structure of F4/80—with adhesive epidermal growth factor domains at one end and a 7-transmembrane spanning domain at the other—suggests that it may be involved in cell–cell or cell–matrix interactions and may also trigger intracellular signaling. The presence of F4/80+ cells in other immune privileged sites, such as the brain and placenta, and its exclusion from T cell zones in the spleen suggests that F4/80 expression and immune activation may be mutually exclusive.