Work

Interferon Regulatory Factor 2 ( IRF2 ) Suppression Enhances Murine Cardiac Allograft Survival Through Immune Evasion

Year: 2025

Type: article

Abstract: ABSTRACT Transplant rejection, primarily caused by the immune system's recognition of allografts, continues to pose a significant challenge to graft survival. Drawing inspiration from the function of interferon regulatory factor 2 (IRF2) in tumour immune evasion, we explored its potential role in the context of transplantation. We quantified the expression of MHC‐I, PD‐L1 and associated molecules in cardiac tissues of IRF2 KO mice through RNA and protein analyses. Subsequently, we established a murine heterotopic cardiac transplantation model using IRF2‐KO donors to evaluate the role of IRF2 in post‐transplant survival. Immunofluorescence and immunohistochemical staining revealed IRF2‐dependent regulation of MHC‐I and PD‐L1 in grafts, accompanied by altered CD4 + /CD8 + T‐cell infiltration patterns. Further, in vitro experiments employing RNA interference (RNAi) in cardiomyocytes demonstrated IRF2‐mediated control of MHC‐I/PD‐L1 expression and its functional impact on T‐cell proliferation and apoptosis in co‐culture systems. In mice heart tissues, as revealed by the transcriptome sequencing, IRF2 knockdown downregulated immune‐related pathways (MHC, inflammation) and upregulated apoptosis‐linked pathways. IRF2 deficiency enhances PD‐L1 and suppresses TAP2/ERAP1‐MHC‐I axis at RNA and protein levels. After transplantation, IRF2 deficiency in allografts prolongs survival by attenuating CD4 + /CD8 + T‐cell infiltration via PD‐L1 upregulation and MHC‐I downregulation, thereby mitigating inflammatory injury. In vitro, IRF2 knockdown in HL‐1 murine cardiomyocytes via siRNA upregulated PD‐L1 expression, suppressed TAP2/ERAP1 levels and attenuated T‐cell proliferation while promoting apoptosis in co‐culture systems. We elucidate the principal mechanism underlying IRF2‐mediated allograft immune evasion, thereby identifying its targeted modulation as an innovative therapeutic approach to prevent early acute rejection and diminish long‐term reliance on immunosuppressive therapy in transplantation.

Source: Immunology

DOI: 10.1111/imm.70082

Authors: Li Tian, Man Zhang, Yuliang Guo, Sheng Chang, Zhonghua Klaus Chen, Hongmin Zhou

Institutions: Chinese Academy of Medical Sciences & Peking Union Medical College, Tongji Hospital, Huazhong University of Science and Technology

Language: English

Topic: Transplantation: Methods and Outcomes

Subfield: Surgery

Field: Medicine

Domain: Health Sciences

SDG: Good health and well-being

Open Access status: hybrid

Estimated APC paid: $5,330