PD-L1 regulates the development, maintenance, and function of induced regulatory T cells

Francisco, et al. 2009. J. Exp. Med. 206, 3015-3029

Speaker: Tzu-Hao Yeh (葉子豪)                           Time: 15:10~16:00, May 19, 2010

Commentator: Dr. Li-Jin Hsu (徐麗君 老師)      Place: Room 601

Abstract:

Programmed death-1 (PD-1) is an inhibitory receptor expressed on activated lymphocytes, and its ligands (PD-Ls) can be expressed broadly on various cells including antigen- presenting cells (APCs). The interaction between PD-1 and PD-L1 is important for development of T cell tolerance [1]. PD-1 has also been detected on regulatory T (Treg) cells, an immunosuppressive T cell subset that plays substantial roles in tissue tolerance, but whether the PD-L1-PD-1 pathway regulates Treg cells remains unclear. In this study, the authors identify a direct linkage between PD-L1 and Treg cells. First, development of induced Treg (iTreg) cells in vitro is reduced when cocultured APCs do not express PD-L1. In an APC-free condition, PD-L1-coated beads can cooperate with transforming growth factor-b to promote iTreg development synergistically, and the PD-L1-induced Treg cells suppress effector T cell proliferation more effectively than control iTreg cells. PD-L1-treated T cells show enhanced expression of PTEN and reduced phosphorylation of Akt, mTOR and S6, suggesting that PD-L1 may antagonize the Akt-mTOR signaling pathway to potentiate Treg cell development. After initial iTreg development, PD-L1 also maintains Foxp3 expression and enhances suppressive function of established iTreg cells. In a mouse model, adoptive transfer of naïve CD4 T cells into PD-L1^-/-PD-L2^-/-Rag^-/- recipients results in large reduction of Treg conversion without affecting Th1 and Th17 populations. The decrease of iTreg cells is accompanied by severe inflammation in lungs and high mortality. Therefore, this study provides in vitro and in vivo data to demonstrate that PD-L1 is important for development, maintenance and biologic function of iTreg cells. The PD-L1-PD-1-Treg linkage brings more insights to autoimmune diseases, chronic infections and cancers.

Reference:

1.          Keir, et al. PD-1 and Its Ligands in Tolerance and Immunity. Annu. Rev. Immunol. 26, 677–704 (2008)