CD4+CD25+ T regulatory cells activated during feline immunodeficiency virus infection convert T helper cells into functional suppressors through a membrane-bound TGFβ/GARP-mediated mechanism

Background: We and others have previously reported that cell membrane-bound TGF beta (mTGF beta) on activated T regulatory (Treg) cells mediates suppressor function. Current findings suggest that a novel protein known as Glycoprotein A Repetitions Predominant (GARP) anchors mTGF beta to the Treg cell surface and facilitates suppressor activity. Recently, we have described that GARP(+)TGF beta(+) Treg cells expand during the course of FIV infection. Because Treg cells are anergic and generally exhibit poor proliferative ability, we asked how Treg homeostasis is maintained during the course of feline immunodeficiency virus (FIV) infection. Results: Here, we report that Treg cells from FIV+ cats express GARP and mTGF beta and convert T helper (Th) cells into phenotypic and functional Treg cells. Th to Treg conversion was abrogated by anti-TGF beta or anti-GARP treatment of Treg cells or by anti-TGF beta RII treatment of Th cells, suggesting that Treg cell recruitment from the Th pool is mediated by TGF beta/TGF beta RII signaling and that cell-surface GARP plays a major role in this process. Conclusions: These findings suggest Th to Treg conversion may initiate a cascade of events that contributes to the maintenance of virus reservoirs, progressive Th cell immunosuppression, and the development of immunodeficiency, all of which are central to the pathogenesis of AIDS lentivirus infections.