FIV infection activates Regulatory T cells expressing GARP-bound TGFb complexes which suppress T helper cells and may contribute to immune dysfunction

Abstract Here we identify on feline Treg cells Glycoprotein A Repititions Predominant (GARP), a cell surface anchor for TGFb, as a functional protein in Treg-mediated suppression. We demonstrate co-precipitation of mature TGFb with GARP from feline CD4+CD25+ cells. The GARP:TGFb complex is expressed on the surface of highly effective suppressors, as depletion of these cells from the Treg pool reduces suppression of CD4+CD25- targets as measured by IL2 inhibition. In vitro activation of CD4+CD25+ cells upregulates surface GARP:TGFb as measured by flow cytometry. Surface phenotyping of PBMCs from noninfected or chronically FIV-infected cats reveals a higher percent of GARP+TGFb+ Tregs and of TGFbRII+ T helper targets in FIV+ cats. At days 3 or 6 post in vitro FIV infection CD4+CD25+ cells upregulate GARP:TGFb and CD4+CD25- upregulate TGFbRII. In vivo infection studies were performed and expression of GARP, TGFb or TGFbRII was evaluated on PBMC for 13 weeks post infection. Acute FIV infection generated increased GARP:TGFb expression on CD4+CD25+ cells one week post infection and a corresponding increase in TGFbRII on CD4+CD25- consistent with in vitro study results. We conclude that GARP: TGFb is increased on the surface of Treg cells during acute FIV and contributes to the CD4+ T cell anergy via ligation of TGFbRII on the surface of CD4+CD25- T helpers. We hypothesize that FIV infects Treg cells in vivo, resulting in activation of these suppressor cells and chronic T helper dysfunction.