Inhibition of interferon regulatory factor 4 orchestrates T cell dysfunction, extending mouse cardiac allograft survival.
10.1097/CM9.0000000000003198
- Author:
Wenjia YUAN
1
;
Hedong ZHANG
1
;
Longkai PENG
1
;
Chao CHEN
1
;
Chen FENG
1
;
Zhouqi TANG
1
;
Pengcheng CUI
2
;
Yaguang LI
1
;
Tengfang LI
1
;
Xia QIU
2
;
Yan CUI
2
;
Yinqi ZENG
1
;
Jiadi LUO
3
;
Xubiao XIE
1
;
Yong GUO
1
;
Xin JIANG
4
;
Helong DAI
1
Author Information
1. Department of Kidney Transplantation, Center of Organ Transplantation, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China.
2. Medical College, Guangxi University, Nanning, Guangxi 530004, China.
3. Department of Pathology, The Second Xiangya Hospital of Central South University, Changsha, Hunan 410011, China.
4. Department of Organ Transplantation, The Fifth Clinical Medical College of Henan University of Chinese Medicine (Zhengzhou People's Hospital), Zhengzhou, Henan 450000, China.
- Publication Type:Journal Article
- Keywords:
Interferon regulatory factor 4;
Mammalian target of rapamycin;
Mitogen-activated protein kinase;
Mouse cardiac transplantation;
Programmed death-1;
Rapamycin;
T cell dysfunction;
Trametinib
- MeSH:
Animals;
Mice;
Mice, Inbred BALB C;
Mice, Inbred C57BL;
Interferon Regulatory Factors/metabolism*;
Heart Transplantation/methods*;
T-Lymphocytes/immunology*;
Sirolimus/therapeutic use*;
Pyridones/therapeutic use*;
Graft Survival/drug effects*;
Pyrimidinones/therapeutic use*;
Cell Proliferation/drug effects*;
Apoptosis/drug effects*;
Male;
Signal Transduction/drug effects*
- From:
Chinese Medical Journal
2025;138(10):1202-1212
- CountryChina
- Language:English
-
Abstract:
BACKGROUND:T cell dysfunction, which includes exhaustion, anergy, and senescence, is a distinct T cell differentiation state that occurs after antigen exposure. Although T cell dysfunction has been a cornerstone of cancer immunotherapy, its potential in transplant research, while not yet as extensively explored, is attracting growing interest. Interferon regulatory factor 4 (IRF4) has been shown to play a pivotal role in inducing T cell dysfunction.
METHODS:A novel ultra-low-dose combination of Trametinib and Rapamycin, targeting IRF4 inhibition, was employed to investigate T cell proliferation, apoptosis, cytokine secretion, expression of T-cell dysfunction-associated molecules, effects of mitogen-activated protein kinase (MAPK) and mammalian target of rapamycin (mTOR) signaling pathways, and allograft survival in both in vitro and BALB/c to C57BL/6 mouse cardiac transplantation models.
RESULTS:In vitro , blockade of IRF4 in T cells effectively inhibited T cell proliferation, increased apoptosis, and significantly upregulated the expression of programmed cell death protein 1 (PD-1), Helios, CD160, and cytotoxic T lymphocyte-associated antigen (CTLA-4), markers of T cell dysfunction. Furthermore, it suppressed the secretion of pro-inflammatory cytokines interferon (IFN)-γ and interleukin (IL)-17. Combining ultra-low-dose Trametinib (0.1 mg·kg -1 ·day -1 ) and Rapamycin (0.1 mg·kg -1 ·day -1 ) demonstrably extended graft survival, with 4 out of 5 mice exceeding 100 days post-transplantation. Moreover, analysis of grafts at day 7 confirmed sustained IFN regulatory factor 4 (IRF4) inhibition, enhanced PD-1 expression, and suppressed IFN-γ secretion, reinforcing the in vivo efficacy of this IRF4-targeting approach. The combination of Trametinib and Rapamycin synergistically inhibited the MAPK and mTOR signaling network, leading to a more pronounced suppression of IRF4 expression.
CONCLUSIONS:Targeting IRF4, a key regulator of T cell dysfunction, presents a promising avenue for inducing transplant immune tolerance. In this study, we demonstrate that a novel ultra-low-dose combination of Trametinib and Rapamycin synergistically suppresses the MAPK and mTOR signaling network, leading to profound IRF4 inhibition, promoting allograft acceptance, and offering a potential new therapeutic strategy for improved transplant outcomes. However, further research is necessary to elucidate the underlying pharmacological mechanisms and facilitate translation to clinical practice.
