Interleukin 27(IL-27),a heterodimeric cytokine composed of Epstein-Barr virus-induced 3 and p28,is a pleiotropic cytokine with both pro-and anti-inflammatory properties.However,the precise role of IL-27 in acute graft...Interleukin 27(IL-27),a heterodimeric cytokine composed of Epstein-Barr virus-induced 3 and p28,is a pleiotropic cytokine with both pro-and anti-inflammatory properties.However,the precise role of IL-27 in acute graft-versus-host disease is not yet fully understood.In this study,utilizing mice with IL-27 p28 deficiency in dendritic cells(DCs),we demonstrated that IL-27 p28 deficiency resulted in impaired Treg cell function and enhanced effector T cell responses,corresponding to aggravated aGVHD in mice.In addition,using single-cell RNA sequencing,we found that loss of IL-27 p28 impaired Treg cell generation and promoted IL1R2^(+)TIGIT^(+)pathogenic CD4+T cells in the thymus at a steady state.Mechanistically,IL-27 p28 deficiency promoted STAT1 phosphorylation and Th1 cell responses,leading to the inhibition of Treg cell differentiation and function.Finally,patients with high levels of IL-27 p28 in serum showed a substantially decreased occurrence of grade II-IV aGVHD and more favorable overall survival than those with low levels of IL-27 p28.Thus,our results suggest a protective role of DC-derived IL-27 p28 in the pathogenesis of aGVHD through modulation of the Treg/Teff cell balance during thymic development.IL-27 p28 may be a valuable marker for predicting aGVHD development after transplantation in humans.展开更多
基金supported by the National Natural Science Foundation of China(No.81730003,81700173,81974001,82170222,and 81900180)National Science and Technology Major Project(2017ZX09304021)+9 种基金National Key R&D Program of China(2019YFC0840604 and 2017YFA0104502)Key R&D Program of Jiangsu Province(BE2019798)Priority Academic Program Development of Jiangsu Higher Education Institutions(PAPD),Jiangsu Medical Outstanding Talents Project(JCRCA2016002)Jiangsu Provincial Key Medical Center(YXZXA2016002)the Jiangsu“333”Talent Project(BRA2015497)the Jiangsu Social Development Program(BE2018651)the Jiangsu Summit Six Top Talent Person project,Jiangsu Medical Junior Talent Person award(QNRC2016707)Natural Science Foundation of Jiangsu Province(BK20220246),Suzhou Science and Technology Program Project(SLT201911)the Natural Science Foundation of Jiangsu Higher Education Institutions of China(20KJD320001)Natural Science Basic Research Program of Shaanxi(2022JQ-800).
文摘Interleukin 27(IL-27),a heterodimeric cytokine composed of Epstein-Barr virus-induced 3 and p28,is a pleiotropic cytokine with both pro-and anti-inflammatory properties.However,the precise role of IL-27 in acute graft-versus-host disease is not yet fully understood.In this study,utilizing mice with IL-27 p28 deficiency in dendritic cells(DCs),we demonstrated that IL-27 p28 deficiency resulted in impaired Treg cell function and enhanced effector T cell responses,corresponding to aggravated aGVHD in mice.In addition,using single-cell RNA sequencing,we found that loss of IL-27 p28 impaired Treg cell generation and promoted IL1R2^(+)TIGIT^(+)pathogenic CD4+T cells in the thymus at a steady state.Mechanistically,IL-27 p28 deficiency promoted STAT1 phosphorylation and Th1 cell responses,leading to the inhibition of Treg cell differentiation and function.Finally,patients with high levels of IL-27 p28 in serum showed a substantially decreased occurrence of grade II-IV aGVHD and more favorable overall survival than those with low levels of IL-27 p28.Thus,our results suggest a protective role of DC-derived IL-27 p28 in the pathogenesis of aGVHD through modulation of the Treg/Teff cell balance during thymic development.IL-27 p28 may be a valuable marker for predicting aGVHD development after transplantation in humans.
