The PD-Ligand Pathway regulates the development, maintenance and function of induced regulatory T cells in vitro and in vivo (49.16)

Autor: Loise Francisco, Victor Salinas, Keturah Brown, Vijay Vanguri, Gordon Freeman, Vijay Kuchroo, Arlene Sharpe
Rok vydání: 2010
Předmět:
Zdroj: The Journal of Immunology. 184:49.16-49.16
ISSN: 1550-6606
0022-1767
DOI: 10.4049/jimmunol.184.supp.49.16
Popis: Both the PD-1:PD-Ligand pathway and regulatory T cells (Tregs) are instrumental to the maintenance of peripheral tolerance. PD-1 has two ligands, PD-L1 and PD-L2. We demonstrate that PD-L1 plays a pivotal role in the de novo differentiation of regulatory T cells and the maintenance of Treg function. PD-L1-/- APCs minimally convert naïve CD4 T cells to become induced-regulatory T cells (iTregs). Moreover, PD-L1-coated beads profoundly increase the CD4+Foxp3+ Treg population, mediated by attenuation of the Akt-mTOR axis and concomitant with upregulation of PTEN. These PD-L1-iTregs suppress T effector cell proliferation more efficiently than control-iTregs and express high levels of CD25, PD-1, B7-1 and GITR. Furthermore, when control or PD-L1-induced Tregs are sorted and re-cultured with PD-L1-coated beads, PD-L1 enhances Foxp3 expression and suppressive function of iTregs. The obligatory role for PD-L1 in controlling iTreg development and function in vivo is illustrated by a marked reduction in iTreg conversion and rapid onset of a fatal inflammatory phenotype in PD-Ligand-/- Rag-/- recipients of naïve CD4 T cells. Parallel studies with PD-L2 reveal similar effects on the de novo differentiation of iTregs. Thus, the PD-1:PD-Ligand pathway can inhibit T cell responses by promoting both the induction and maintenance of induced Tregs. These studies define a novel mechanism for iTreg development and function, as well as a new strategy for controlling Treg plasticity.
Databáze: OpenAIRE