The GARP/Latent TGF-β1 complex on Treg cells modulates the induction of peripherally derived Treg cells during oral tolerance

Treg cells can secrete latent TGF-beta 1 (LTGF-beta 1), but can also utilize an alternative pathway for transport and expression of LTGF-beta 1 on the cell surface in which LTGF-beta 1 is coupled to a distinct LTGF-beta binding protein termed glycoprotein A repetitions predominant (GARP)/LRRC32. The function of the GARP/LTGF-beta 1 complex has remained elusive. Here, we examine in vivo the roles of GARP and TGF-beta 1 in the induction of oral tolerance. When Foxp3(-) OT-II T cells were transferred to wild-type recipient mice followed by OVA feeding, the conversion of Foxp3(-) to Foxp3(+) OT-II cells was dependent on recipient Treg cells. Neutralization of IL-2 in the recipient mice also abrogated this conversion. The GARP/LTGF-beta 1 complex on recipient Treg cells, but not dendritic cell-derived TGF-beta 1, was required for efficient induction of Foxp3(+) T cells and for the suppression of delayed hypersensitivity. Expression of the integrin alpha v beta 8 by Treg cells (or T cells) in the recipients was dispensable for induction of Foxp3 expression. Transient depletion of the bacterial flora enhanced the development of oral tolerance by expanding Treg cells with enhanced expression of the GARP/LTGF-beta 1 complex.