| T regulatory (Treg) cells are key players in maintaining peripheral tolerance and preventing autoimmune diseases. We aimed to delineate the mechanisms of human Treg-mediated suppression. We found that strength of T cell receptor (TCR) signals and Treg to target ratios are critical parameters for efficient suppression. To identify novel molecules that mediate Treg function, we performed a microarray analysis and discovered a molecule that is specifically expressed on cell surface of activated human Tregs. We demonstrated that this molecule, called GARP, can account for part of Treg suppressive activity. The development of Tregs depends on a master transcription named Foxp3. Indeed, we had shown that high level of Foxp3 expression is required for Treg suppressive function but not their hypo-responsiveness to TCR stimulation. However, not all Foxp3-expressing human T cells are suppressors. Remarkably, we found that expression of GARP also marks T cells with suppressive potential and discriminates suppressor Tregs from T cells that express Foxp3 through induction via TGFbeta and T cell receptor signaling. Thus, GARP provides a novel tool to assess Treg subset in patients with chronic inflammatory diseases, such as HIV infection. Together, our findings provide mechanistic insight to human Treg function and suggest novel strategies to manipulate or identify Tregs during unwanted immune responses. |
