Donor T cell STAT3 deficiency enables tissue PD-L1–dependent prevention of graft-versus-host disease while preserving graft-versus-leukemia activity
STAT3 deficiency (STAT3–/–) in donor T cells prevents graft-versus-host disease (GVHD), but the impact on graft-versus-leukemia (GVL) activity and mechanisms of GVHD prevention remains unclear. Here, using murine models of GVHD, we show that STAT3–/– donor T cells induced only mild reversible acute...
| Main Authors: | , , , , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
American Society for Clinical Investigation
2023-08-01
|
| Series: | The Journal of Clinical Investigation |
| Subjects: | |
| Online Access: | https://doi.org/10.1172/JCI165723 |
| _version_ | 1797634453220098048 |
|---|---|
| author | Qinjian Li Xiaoqi Wang Qingxiao Song Shijie Yang Xiwei Wu Dongyun Yang Isabelle J. Marié Hanjun Qin Moqian Zheng Ubaydah Nasri Xiaohui Kong Bixin Wang Elizabeth Lizhar Kaniel Cassady Josh Tompkins David Levy Paul J. Martin Xi Zhang Defu Zeng |
| author_facet | Qinjian Li Xiaoqi Wang Qingxiao Song Shijie Yang Xiwei Wu Dongyun Yang Isabelle J. Marié Hanjun Qin Moqian Zheng Ubaydah Nasri Xiaohui Kong Bixin Wang Elizabeth Lizhar Kaniel Cassady Josh Tompkins David Levy Paul J. Martin Xi Zhang Defu Zeng |
| author_sort | Qinjian Li |
| collection | DOAJ |
| description | STAT3 deficiency (STAT3–/–) in donor T cells prevents graft-versus-host disease (GVHD), but the impact on graft-versus-leukemia (GVL) activity and mechanisms of GVHD prevention remains unclear. Here, using murine models of GVHD, we show that STAT3–/– donor T cells induced only mild reversible acute GVHD while preserving GVL effects against nonsusceptible acute lymphoblastic leukemia (ALL) cells in a donor T cell dose–dependent manner. GVHD prevention depended on programmed death ligand 1/programmed cell death protein 1 (PD-L1/PD-1) signaling. In GVHD target tissues, STAT3 deficiency amplified PD-L1/PD-1 inhibition of glutathione (GSH)/Myc pathways that regulate metabolic reprogramming in activated T cells, with decreased glycolytic and mitochondrial ATP production and increased mitochondrial ROS production and dysfunction, leading to tissue-specific deletion of host-reactive T cells and prevention of GVHD. Mitochondrial STAT3 deficiency alone did not reduce GSH expression or prevent GVHD. In lymphoid tissues, the lack of host-tissue PD-L1 interaction with PD-1 reduced the inhibition of the GSH/Myc pathway despite reduced GSH production caused by STAT3 deficiency and allowed donor T cell functions that mediate GVL activity. Therefore, STAT3 deficiency in donor T cells augments PD-1 signaling–mediated inhibition of GSH/Myc pathways and augments dysfunction of T cells in GVHD target tissues while sparing T cells in lymphoid tissues, leading to prevention of GVHD while preserving GVL effects. |
| first_indexed | 2024-03-11T12:08:03Z |
| format | Article |
| id | doaj.art-aff5b3ae62254d4ba378147ae1971705 |
| institution | Directory Open Access Journal |
| issn | 1558-8238 |
| language | English |
| last_indexed | 2024-03-11T12:08:03Z |
| publishDate | 2023-08-01 |
| publisher | American Society for Clinical Investigation |
| record_format | Article |
| series | The Journal of Clinical Investigation |
| spelling | doaj.art-aff5b3ae62254d4ba378147ae19717052023-11-07T16:20:41ZengAmerican Society for Clinical InvestigationThe Journal of Clinical Investigation1558-82382023-08-0113315Donor T cell STAT3 deficiency enables tissue PD-L1–dependent prevention of graft-versus-host disease while preserving graft-versus-leukemia activityQinjian LiXiaoqi WangQingxiao SongShijie YangXiwei WuDongyun YangIsabelle J. MariéHanjun QinMoqian ZhengUbaydah NasriXiaohui KongBixin WangElizabeth LizharKaniel CassadyJosh TompkinsDavid LevyPaul J. MartinXi ZhangDefu ZengSTAT3 deficiency (STAT3–/–) in donor T cells prevents graft-versus-host disease (GVHD), but the impact on graft-versus-leukemia (GVL) activity and mechanisms of GVHD prevention remains unclear. Here, using murine models of GVHD, we show that STAT3–/– donor T cells induced only mild reversible acute GVHD while preserving GVL effects against nonsusceptible acute lymphoblastic leukemia (ALL) cells in a donor T cell dose–dependent manner. GVHD prevention depended on programmed death ligand 1/programmed cell death protein 1 (PD-L1/PD-1) signaling. In GVHD target tissues, STAT3 deficiency amplified PD-L1/PD-1 inhibition of glutathione (GSH)/Myc pathways that regulate metabolic reprogramming in activated T cells, with decreased glycolytic and mitochondrial ATP production and increased mitochondrial ROS production and dysfunction, leading to tissue-specific deletion of host-reactive T cells and prevention of GVHD. Mitochondrial STAT3 deficiency alone did not reduce GSH expression or prevent GVHD. In lymphoid tissues, the lack of host-tissue PD-L1 interaction with PD-1 reduced the inhibition of the GSH/Myc pathway despite reduced GSH production caused by STAT3 deficiency and allowed donor T cell functions that mediate GVL activity. Therefore, STAT3 deficiency in donor T cells augments PD-1 signaling–mediated inhibition of GSH/Myc pathways and augments dysfunction of T cells in GVHD target tissues while sparing T cells in lymphoid tissues, leading to prevention of GVHD while preserving GVL effects.https://doi.org/10.1172/JCI165723HematologyTransplantation |
| spellingShingle | Qinjian Li Xiaoqi Wang Qingxiao Song Shijie Yang Xiwei Wu Dongyun Yang Isabelle J. Marié Hanjun Qin Moqian Zheng Ubaydah Nasri Xiaohui Kong Bixin Wang Elizabeth Lizhar Kaniel Cassady Josh Tompkins David Levy Paul J. Martin Xi Zhang Defu Zeng Donor T cell STAT3 deficiency enables tissue PD-L1–dependent prevention of graft-versus-host disease while preserving graft-versus-leukemia activity The Journal of Clinical Investigation Hematology Transplantation |
| title | Donor T cell STAT3 deficiency enables tissue PD-L1–dependent prevention of graft-versus-host disease while preserving graft-versus-leukemia activity |
| title_full | Donor T cell STAT3 deficiency enables tissue PD-L1–dependent prevention of graft-versus-host disease while preserving graft-versus-leukemia activity |
| title_fullStr | Donor T cell STAT3 deficiency enables tissue PD-L1–dependent prevention of graft-versus-host disease while preserving graft-versus-leukemia activity |
| title_full_unstemmed | Donor T cell STAT3 deficiency enables tissue PD-L1–dependent prevention of graft-versus-host disease while preserving graft-versus-leukemia activity |
| title_short | Donor T cell STAT3 deficiency enables tissue PD-L1–dependent prevention of graft-versus-host disease while preserving graft-versus-leukemia activity |
| title_sort | donor t cell stat3 deficiency enables tissue pd l1 dependent prevention of graft versus host disease while preserving graft versus leukemia activity |
| topic | Hematology Transplantation |
| url | https://doi.org/10.1172/JCI165723 |
| work_keys_str_mv | AT qinjianli donortcellstat3deficiencyenablestissuepdl1dependentpreventionofgraftversushostdiseasewhilepreservinggraftversusleukemiaactivity AT xiaoqiwang donortcellstat3deficiencyenablestissuepdl1dependentpreventionofgraftversushostdiseasewhilepreservinggraftversusleukemiaactivity AT qingxiaosong donortcellstat3deficiencyenablestissuepdl1dependentpreventionofgraftversushostdiseasewhilepreservinggraftversusleukemiaactivity AT shijieyang donortcellstat3deficiencyenablestissuepdl1dependentpreventionofgraftversushostdiseasewhilepreservinggraftversusleukemiaactivity AT xiweiwu donortcellstat3deficiencyenablestissuepdl1dependentpreventionofgraftversushostdiseasewhilepreservinggraftversusleukemiaactivity AT dongyunyang donortcellstat3deficiencyenablestissuepdl1dependentpreventionofgraftversushostdiseasewhilepreservinggraftversusleukemiaactivity AT isabellejmarie donortcellstat3deficiencyenablestissuepdl1dependentpreventionofgraftversushostdiseasewhilepreservinggraftversusleukemiaactivity AT hanjunqin donortcellstat3deficiencyenablestissuepdl1dependentpreventionofgraftversushostdiseasewhilepreservinggraftversusleukemiaactivity AT moqianzheng donortcellstat3deficiencyenablestissuepdl1dependentpreventionofgraftversushostdiseasewhilepreservinggraftversusleukemiaactivity AT ubaydahnasri donortcellstat3deficiencyenablestissuepdl1dependentpreventionofgraftversushostdiseasewhilepreservinggraftversusleukemiaactivity AT xiaohuikong donortcellstat3deficiencyenablestissuepdl1dependentpreventionofgraftversushostdiseasewhilepreservinggraftversusleukemiaactivity AT bixinwang donortcellstat3deficiencyenablestissuepdl1dependentpreventionofgraftversushostdiseasewhilepreservinggraftversusleukemiaactivity AT elizabethlizhar donortcellstat3deficiencyenablestissuepdl1dependentpreventionofgraftversushostdiseasewhilepreservinggraftversusleukemiaactivity AT kanielcassady donortcellstat3deficiencyenablestissuepdl1dependentpreventionofgraftversushostdiseasewhilepreservinggraftversusleukemiaactivity AT joshtompkins donortcellstat3deficiencyenablestissuepdl1dependentpreventionofgraftversushostdiseasewhilepreservinggraftversusleukemiaactivity AT davidlevy donortcellstat3deficiencyenablestissuepdl1dependentpreventionofgraftversushostdiseasewhilepreservinggraftversusleukemiaactivity AT pauljmartin donortcellstat3deficiencyenablestissuepdl1dependentpreventionofgraftversushostdiseasewhilepreservinggraftversusleukemiaactivity AT xizhang donortcellstat3deficiencyenablestissuepdl1dependentpreventionofgraftversushostdiseasewhilepreservinggraftversusleukemiaactivity AT defuzeng donortcellstat3deficiencyenablestissuepdl1dependentpreventionofgraftversushostdiseasewhilepreservinggraftversusleukemiaactivity |