Transforming growth factor-β/transforming growth factor-βRII signaling may regulate CD4+CD25+ T-regulatory cell homeostasis and suppressor function in feline AIDS lentivirus infection

We have reported that CD4(+)CD25(+) T-regulatory (Treg) cells are fully activated for suppressor function in feline immunodeficiency virus (FIV)-infected cats. Studies have suggested that surface transforming growth factor-P (TGF beta; membrane TGF beta [mTGF beta]) is a feature of activated CD4(+)CD25(+) Treg cells and may play a role in Treg homeostasis and suppressor function. Herein, we explore the role of TGF beta in feline Treg homeostasis and suppressor function and what effect FIV infection of cats might have on these processes. Stimulation of CD4(+)CD25(-) T helper (Th) cells with Concanavalin A (ConA) plus TGF beta converts them to Treg-like cells capable of suppressor function. Reverse-transcription polymerase chain reaction and flow cytometry revealed that these ConA/TGF beta-converted Treg cells upregulate Foxp3 and mTGF beta, ConA stimulation of CD4(+)CD25(-)T cells upregulates TGF beta receptor II (RII), and pretreatment of these cells with anti-TGF beta-RII antibodies blocks the TGF beta-induced conversion to Treg cells. Pretreatment of ConA/TGF beta-converted Treg cells with anti-TGF beta antibodies also abrogates their suppressor function, suggesting that Treg homeostasis and suppressor function may be mediated by mTGF beta. Finally, we show that treatment of CD4(+)CD25(+) mTGF beta-positive Treg cells from FIV-infected cats with anti-TGF beta antibodies or treatment of ConA-stimulated CD4(+)CD25(-) Th target cells with anti-TGF beta-RII antibodies diminishes suppressor function. These data suggest that the recruitment of Treg cells from the Th pool and suppressor function of Treg cells are dependent on the TGF beta/TGF beta-RIII signaling pathway and that this pathway is constitutively upregulated in asymptomatic chronically FIV-infected cats.