Programmed cell death 1 (PD-1) regulates the effector function of CD8 T cells via PD-L1 expressed on target keratinocytes |
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Institution: | 1. Iran University of Medical Sciences, Medical School, Biochemistry Department, Iran;2. Iran University of Medical Sciences, School of Medicine-International Branch, Iran;3. Iran University of Medical Sciences, Cellular and Molecular Research Center, Iran;1. Department of Orthopedic Surgery, Yonsei University College of Medicine, Seoul, South Korea;2. Department of Orthopedic Surgery, International St. Mary''s Hospital, Catholic-Kwandong University, Incheon, South Korea |
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Abstract: | Programmed cell death 1 (PD-1) is an inhibitory molecule expressed by activated T cells. Its ligands (PD-L1 and -L2; PD-Ls) are expressed not only by a variety of leukocytes but also by stromal cells. To assess the role of PD-1 in CD8 T cell-mediated diseases, we used PD-1-knockout (KO) OVA-specific T cell-receptor transgenic (Tg) CD8 T cells (OT-I cells) in a murine model of mucocutaneous graft-versus-host disease (GVHD). We found that mice expressing OVA on epidermal keratinocytes (K14-mOVA mice) developed markedly enhanced GVHD-like disease after transfer of PD-1-KO OT-I cells as compared to those mice transferred with wild-type OT-I cells. In addition, K14-mOVA × OT-I double Tg (DTg) mice do not develop GVHD-like disease after adoptive transfer of OT-I cells, while transfer of PD-1-KO OT-I cells caused GVHD-like disease in a Fas/Fas-L independent manner. These results suggest that PD-1/PD-Ls-interactions have stronger inhibitory effects on pathogenic CD8 T cells than does Fas/Fas-L-interactions. Keratinocytes from K14-mOVA mice with GVHD-like skin lesions express PD-L1, while those from mice without the disease do not. These findings reflect the fact that primary keratinocytes express PD-L1 when stimulated by interferon-γ in vitro. When co-cultured with K14-mOVA keratinocytes for 2 days, PD-1-KO OT-I cells exhibited enhanced proliferation and activation compared to wild-type OT-I cells. In addition, knockdown of 50% PD-L1 expression on the keratinocytes with transfection of PD-L1-siRNA enhanced OT-I cell proliferation. In aggregate, our data strongly suggest that PD-L1, expressed on activated target keratinocytes presenting autoantigens, regulates autoaggressive CD8 T cells, and inhibits the development of mucocutaneous autoimmune diseases. |
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Keywords: | Programmed cell death 1 Programmed cell death ligand 1 Fas Keratinocyte CD8 T cell Graft-versus-host-disease K14-mOVA mouse"} {"#name":"keyword" "$":{"id":"kwrd0045"} "$$":[{"#name":"text" "_":"keratin 14 promoter-membrane ovalbumin-transgenic mouse GVHD"} {"#name":"keyword" "$":{"id":"kwrd0055"} "$$":[{"#name":"text" "_":"graft-versus-host disease DTg mouse"} {"#name":"keyword" "$":{"id":"kwrd0065"} "$$":[{"#name":"text" "_":"K14-mOVA/OT-I double transgenic mouse DN T cell"} {"#name":"keyword" "$":{"id":"kwrd0075"} "$$":[{"#name":"text" "$$":[{"#name":"__text__" "_":"double negative T cell (CD3"} {"#name":"sup" "$":{"loc":"post"} "_":"+"} {"#name":"__text__" "_":"B220"} {"#name":"sup" "$":{"loc":"post"} "_":"?"} {"#name":"__text__" "_":"CD4"} {"#name":"sup" "$":{"loc":"post"} "_":"?"} {"#name":"__text__" "_":"CD8"} {"#name":"sup" "$":{"loc":"post"} "_":"?"} {"#name":"__text__" "_":" cell) SDLN"} {"#name":"keyword" "$":{"id":"kwrd0085"} "$$":[{"#name":"text" "_":"skin-draining lymph node DC"} {"#name":"keyword" "$":{"id":"kwrd0095"} "$$":[{"#name":"text" "_":"dendritic cell LC"} {"#name":"keyword" "$":{"id":"kwrd0105"} "$$":[{"#name":"text" "_":"Langerhans cell KC"} {"#name":"keyword" "$":{"id":"kwrd0115"} "$$":[{"#name":"text" "_":"keratinocyte |
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