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

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.