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.
건선은 흔한 만성 염증성 피부질환이며 건선유발에 가장 중요한 역할을 하는 세포는 인터루킨 17을 분비하는 T 세포이다. 이 세포는 인터루킨 23등의 사이토카인 혹은 T세포 수용체 자극에 의해 활성화된다. 인터루킨 23은 건선치료제의 타겟으로 여겨져 항 p40 길항제 등의 건선치료제가 개발되어 왔다. 하지만 T세포 수용체에 매개되는 염증을 조절할 수 있는 효과적인 건선 약제는 없다. PD-1은 T 세포의 세포 표면에 발현되는 수용체로서 PD-L1과 결합하면 T세포 수용체에 매개되는 신호를 억제시킨다. 또한, PD-1은 반복적인 T세포 수용체 자극에 의해 발현이 증가되는 특징을 지니고 있다. 하지만 건선 내 T 세포에서 PD-1의 역할에 대해서는 아직 밝혀진 바가 없다. 본 실험에서는 이미퀴모드 유발 마우스 모델 및 건선환자의 피부병변 내 인터루킨 17을 분비하는 T세포내 PD-1 발현을 확인하였고, 이들 세포는 PD-L1-Fc 단백질 투여 후 T세포 수용체 자극에 의한 활성이 현저히 감소함을 확인하였다. 또한, PD-L1-Fc는 이미퀴모드 유발 건선염증을 완화시켰으며, 항 p40 길항제와 병합투여 하였을 때 치료효과가 증대되었다.
