(The) role of programmed cell death ligand 1 in the regulation of psoriatic inflammation

Abstract

Psoriasis is one of the most common chronic inflammatory diseases and clinical findings show scal-ing plaques on the erythematous patches on the skin. Recently, interleukine (IL)-17-producing T cells have been shown to play a critical role in psoriatic inflammation. IL-17-producing T cells is activated under the stimulation of cytokines such as IL-23 or T-cell receptor (TCR) engagement. IL-23 has been targeted for treatment of psoriasis using an antibody against p40

however, there is no efficient drug for targeting TCR-mediated activation in psoriasis. Programmed cell death-1 (PD-1) is a co-inhibitory recep-tor expressed on T cells and inhibits TCR-mediated signaling when interacts with programmed cell death ligand 1 (PD-L1) or 2 (PD-L2). Also, PD-1 expression on the cell surface is increased when the cell re-ceive the repetitive TCR stimulation. Nevertheless, it remains to be elucidated whether PD-1 is overex-pressed on T cells in psoriasis and whether PD-1 agonist alleviates psoriatic inflammation. During IMQ-induced psoriatic inflammation, PD-1 is overexpressed on $CD27-V\gamma 1- \gamma \delta T$ cells. In the $CD27-V \gamma 1- \gamma \delta T$ cell population, $V \gamma 4- \gamma \delta T$ cells with $V \gamma 6 mRNA$ expression showed a high level of PD-1 expression. Further, these $PD-1^{hi}V \gamma 4^-(V \gamma 6^+) \gamma \delta T$ cells were specialized for TCR-induced IL-17A produc-tion, which was inhibited by PD-L1-Fc protein treatment. In IMQ-treated mice, PD-L1-Fc protein reduced psoriatic inflammation when given alone and enhanced the therapeutic effect of anti-p40 when given in combination. Further, PD-1 expression on $IL-17A^+ T$ cells was confirmed in the skin from psoriasis pa-tients. Human PD-L1-Fc protein inhibits IL-17A production and proliferation of $PD-1^+CD4 T$ cells. In conclusion, PD-1 is overexpressed in IL-17A-producing T cells in both IMQ-treated mice and psoriasis patients. PD-1-expressing $IL-17A^+ T$ cells are inhibited by the treatment of PD-L1-Fc protein in mice and human. Moreover, PD-L1-Fc protein alleviates psoriatic inflammation in IMQ-treated mice.