The Tregs' world according to GARP

Naturally occurring CD4⁺CD25^high regulatory T cells (nTreg) are essential for maintaining tolerance. FOXP3 has been established as a molecular marker of nTreg; however, FOXP3 cannot be used as a reliable marker for bona fide human nTreg since effector T cells also up‐regulate FOXP3 expression upon activation. Despite the important function of nTreg, the underlying molecular mechanisms of nTreg‐mediated suppression are far from defined. Previous studies have demonstrated that the TGF‐β latency‐associated peptide (LAP) is expressed on the surface of nTreg, and that immunosuppression can be mediated by membrane TGF‐β; however, it remains unknown how LAP is bound to nTreg and what is the functional significance of its selective expression on activated nTreg. The nTreg's world may now change according to GARP, an orphan toll‐like receptor composed of leucine‐rich repeats. In this issue of the European Journal of Immunology, a study provides further demonstration that GARP is selectively expressed only in activated human nTreg and nTreg cell clones but not in activated effector T cells, confirming GARP as a bona fide nTreg marker. In addition, GARP binds directly to LAP; yet, GARP over‐expression is insufficient to induce modification of latent TGF‐β into active TGF‐β further clarifying its role in nTreg‐mediated suppression.