HDAC1 modulates sepsis-induced immunosuppression by driving the exhaustion of CD8+ T cells
Liu Di, Jiang-bo Fan, Rui Wang, You Li, Wan-da Bi, Si-yuan Huang, Heng-hai Nie, Xi-feng Feng, Hua-cai Zhang, Juan Du, Xiao-fei Huang, An-yong Yu, Zhe Xu, Fei Xia, Jian-xin Jiang, Shuang-shuang Dai, Xiang Xu, Zhen Wang, Ling Zeng
Liu Di, Jiang-bo Fan, Rui Wang, You Li, Wan-da Bi, Si-yuan Huang, Heng-hai Nie, Xi-feng Feng, Hua-cai Zhang, Juan Du, Xiao-fei Huang, An-yong Yu, Zhe Xu, Fei Xia, Jian-xin Jiang, Shuang-shuang Dai, Xiang Xu, Zhen Wang, Ling Zeng
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Research Article Immunology Infectious disease Inflammation

HDAC1 modulates sepsis-induced immunosuppression by driving the exhaustion of CD8+ T cells

Abstract

Sepsis, a systemic inflammatory response to infection, remains a leading cause of mortality in intensive care units, with sepsis-induced immunosuppression being a critical pathophysiological process. In this study, we investigated the role of histone deacetylase 1 (HDAC1) in sepsis-induced CD8+ T cell exhaustion, a key driver of immunosuppression. Clinical analyses of patients with sepsis revealed that reduced peripheral blood lymphocyte levels, particularly CD8+ T cell depletion, strongly correlated with worsened outcomes. In a murine sepsis model, single-cell RNA-Seq revealed a significant decrease in the proportion of CD8+ T cells and an increase in the proportion of exhausted CD8+ T cells in mouse lungs. Adoptive transfer of CD8+ T cells effectively reduced sepsis mortality by preserving organ function. We further demonstrated that HDAC1 expression was significantly upregulated in CD8+ T cells from patients with sepsis. In vitro studies showed that HDAC1 inhibition preserved CD8+ T cell function by maintaining T cell activity and reducing the expression of inhibitory molecules such as PD-1. Pharmacological inhibition of HDAC1 reduced mortality and reversed CD8+ T cell exhaustion by restoring the balance between activator protein-1 (AP-1) and nuclear factor of activated T cells (NFAT). Additionally, we found that HDAC1 directly interacted with NFAT1, promoting its nuclear translocation and further enhancing the expression of inhibitory molecules. Our findings highlight HDAC1 as a potential therapeutic target for sepsis-induced immunosuppression. By elucidating the molecular mechanisms underlying HDAC1-mediated immunosuppression, we have provided potential strategies for developing immunomodulatory therapies for the treatment of sepsis.

Authors

Liu Di, Jiang-bo Fan, Rui Wang, You Li, Wan-da Bi, Si-yuan Huang, Heng-hai Nie, Xi-feng Feng, Hua-cai Zhang, Juan Du, Xiao-fei Huang, An-yong Yu, Zhe Xu, Fei Xia, Jian-xin Jiang, Shuang-shuang Dai, Xiang Xu, Zhen Wang, Ling Zeng

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Figure 3

Adoptive transfer of CD8+ T cells reduces the sepsis mortality rate by preserving organ function.

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Adoptive transfer of CD8+ T cells reduces the sepsis mortality rate by p...
(A) Schematic of the animal experimental procedure. Mice were subjected to CLP followed by intranasal challenge with Streptococcus pneumoniae (Sp) as the second hit (2-hit). (B) Representative flow cytometry plots of CD8+ T cells from the peripheral blood of control, CLP-induced sepsis model, and 2-hit model mice. (C) Comparison of CD4+ and CD8+ T cell proportions in the peripheral blood of healthy control, CLP-induced sepsis model, and 2-hit model mice. (D) Kaplan-Meier survival analysis of septic mice following 2-hit model and/or therapeutic administration of CD8+ T cells (5 × 105 per mouse) or 0.9% saline (n = 63 for saline, n = 37 for CD8+ T cell administration, n = 32 for anti-CD8 antibody administration, n = 24 for isotype antibody administration). (E) Representative H&E-stained lung sections and corresponding histological injury scores (n = 5, original magnification, ×200; scale bar: 100 μm). (F) Serum enzyme activity in the liver, kidney, and heart of 2-hit mice from the CD8+ T cell transfer group, IgG control group, and anti-CD8 group. Data are presented as mean ± SD. Statistical significance was determined using 1-way ANOVA followed by Tukey’s post hoc test (C, E, and F) or log-rank test (D). *P < 0.05, **P < 0.01, ***P < 0.001.