Research ArticleImmunology

The PDL1-PD1 Axis Converts Human TH1 Cells into Regulatory T Cells

Science Translational Medicine  30 Nov 2011:
Vol. 3, Issue 111, pp. 111ra120
DOI: 10.1126/scitranslmed.3003130

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Abstract

Immune surveillance by T helper type 1 (TH1) cells is not only critical for the host response to tumors and infection, but also contributes to autoimmunity and graft-versus-host disease (GVHD) after transplantation. The inhibitory molecule programmed death ligand 1 (PDL1) has been shown to anergize human TH1 cells, but other mechanisms of PDL1-mediated TH1 inhibition such as the conversion of TH1 cells to a regulatory phenotype have not been well characterized. We hypothesized that PDL1 may cause TH1 cells to manifest differentiation plasticity. Conventional T cells or irradiated K562 myeloid tumor cells overexpressing PDL1 converted TBET+ TH1 cells into FOXP3+ regulatory T (Treg) cells in vivo, thereby preventing human-into-mouse xenogeneic GVHD (xGVHD). Either blocking PD1 expression on TH1 cells by small interfering RNA targeting or abrogation of PD1 signaling by SHP1/2 pharmacologic inhibition stabilized TH1 cell differentiation during PDL1 challenge and restored the capacity of TH1 cells to mediate lethal xGVHD. PD1 signaling therefore induces human TH1 cells to manifest in vivo plasticity, resulting in a Treg phenotype that severely impairs cell-mediated immunity. Converting human TH1 cells to a regulatory phenotype with PD1 signaling provides a potential way to block GVHD after transplantation. Moreover, because this conversion can be prevented by blocking PD1 expression or pharmacologically inhibiting SHP1/2, this pathway provides a new therapeutic direction for enhancing T cell immunity to cancer and infection.

Footnotes

  • These authors contributed equally to this work.

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