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Peer-reviewedCC BY 4.0Clinical and Translational Medicine

MEK1/2 Signalling establishes an alloreactive effector T cell program through SMAD4 during cardiac allograft rejection

  • Jiulu Zhao1,2,3
  • Shuan Ran1,2,3
  • Sijie Zhou1,2,3
  • Yuan Li1,2,3
  • Wang Zhan1,2,3
  • Longyong Lai1,2,3
  • Jikai Cui1,2,3,4,5
  • Jiahong Xia1,2,3,4,5
  • Jie Wu1,2,3,4,5
5 affiliations
  1. 1Department of Cardiovascular Surgery, Union Hospital, Tongji Medical College Huazhong University of Science and Technology Wuhan China
  2. 2Center for Translational Medicine, Union Hospital, Tongji Medical College Huazhong University of Science and Technology Wuhan China
  3. 3Institute of Translational Medicine, Tongji Medical College Huazhong University of Science and Technology Wuhan China
  4. 4Hubei Key Laboratory of Biological Targeted Therapy, Union Hospital, Tongji Medical College Huazhong University of Science and Technology Wuhan China
  5. 5Key Laboratory of Organ Transplantation, Ministry of Education; NHC Key Laboratory of Organ Transplantation Key Laboratory of Organ Transplantation Chinese Academy of Medical Sciences Wuhan China
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Abstract

Background: Acute allograft rejection is largely dependent on T cell‐driven immune responses; however, the molecular programs that establish and maintain effector T cell states during rejection remain incompletely defined.

Methods: Single‐cell transcriptomic analysis was conducted to characterize the activation of signalling pathways in T cells during acute allograft rejection. The function of MEK1/2 signalling was evaluated both in vitro and in vivo using mice with targeted deletion of Mek1/2 in T cells and pharmacological inhibition. Phosphoproteomic analysis, immunofluorescence staining, and western blotting were conducted to investigate downstream signalling mechanisms, particularly those involving SMAD4.

Results: Effector CD4 and CD8 T cells exhibited enhanced MEK/ERK pathway activation throughout the rejection process. MEK1/2 inhibition, either via genetic deletion or pharmacological blockade, attenuated T cell activation and effector activity, leading to reduced rejection and prolonged graft survival. Phosphoproteomic analysis identified SMAD4 as a key downstream effector of MEK1/2 signalling. Mechanistically, MEK1/2 deficiency reduced SMAD4 nuclear translocation in activated T cells, accompanied by diminished effector T cell responses.

Conclusions: MEK1/2 signalling regulates T cell activation and effector phenotypes via SMAD4 nuclear translocation in heart transplant rejection. Therapeutic intervention targeting this pathway may contribute to alloimmune response regulation and improve transplant outcomes.

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Cite

BibTeXRIS
BibTeX
@article{zhao2026mek12,
  title = {{MEK1/2 Signalling establishes an alloreactive effector T cell program through SMAD4 during cardiac allograft rejection}},
  author = {Jiulu Zhao and Shuan Ran and Sijie Zhou and Yuan Li and Wang Zhan and Longyong Lai and Jikai Cui and Jiahong Xia and Jie Wu},
  journal = {Clinical and Translational Medicine},
  year = {2026},
  month = oct,
  doi = {10.1002/ctm2.70865},
  url = {https://doi.org/10.1002/ctm2.70865},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - MEK1/2 Signalling establishes an alloreactive effector T cell program through SMAD4 during cardiac allograft rejection
AU  - Jiulu Zhao
AU  - Shuan Ran
AU  - Sijie Zhou
AU  - Yuan Li
AU  - Wang Zhan
AU  - Longyong Lai
AU  - Jikai Cui
AU  - Jiahong Xia
AU  - Jie Wu
PY  - 2026
DA  - 2026/10/27
JO  - Clinical and Translational Medicine
DO  - 10.1002/ctm2.70865
UR  - https://doi.org/10.1002/ctm2.70865
AB  - Background: Acute allograft rejection is largely dependent on T cell‐driven immune responses; however, the molecular programs that establish and maintain effector T cell states during rejection remain incompletely defined.  Methods: Single‐cell transcriptomic analysis was conducted to characterize the activation of signalling pathways in T cells during acute allograft rejection. The function of MEK1/2 signalling was evaluated both in vitro and in vivo using mice with targeted deletion of Mek1/2 in T cells and pharmacological inhibition. Phosphoproteomic analysis, immunofluorescence staining, and western blotting were conducted to investigate downstream signalling mechanisms, particularly those involving SMAD4.  Results: Effector CD4 and CD8 T cells exhibited enhanced MEK/ERK pathway activation throughout the rejection process. MEK1/2 inhibition, either via genetic deletion or pharmacological blockade, attenuated T cell activation and effector activity, leading to reduced rejection and prolonged graft survival. Phosphoproteomic analysis identified SMAD4 as a key downstream effector of MEK1/2 signalling. Mechanistically, MEK1/2 deficiency reduced SMAD4 nuclear translocation in activated T cells, accompanied by diminished effector T cell responses.  Conclusions: MEK1/2 signalling regulates T cell activation and effector phenotypes via SMAD4 nuclear translocation in heart transplant rejection. Therapeutic intervention targeting this pathway may contribute to alloimmune response regulation and improve transplant outcomes.
SN  - 2001-1326
ER  -