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 5

HDAC1 inhibition alleviates CD8+ T cell exhaustion and increases the survival rate of mice.

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HDAC1 inhibition alleviates CD8+ T cell exhaustion and increases the sur...
(A) Schematic timeline of the experimental design. The mice underwent CLP (day 0) followed by intranasal administration of Streptococcus pneumoniae as a second hit (day 3). HDAC inhibitors (HDACis) were i.p. administered after the second hit, and the analyses were performed on day 7. (B) Quantification of CD8+ T cell counts in the peripheral blood of healthy, 2-hit model, and HDACi-treated mice. (C) Kaplan-Meier survival analysis of 2-hit model mice treated with HDACis (n = 25 per group, P = 0.0325). (D) Relative mRNA expression levels of Hdac1, Cd244, and Pdcd1 in splenic CD8+ T cells from CLP-induced sepsis model, 2-hit model, and HDACi-treated mice. (E) Representative flow cytometry histograms showing CD8 and HDAC1 expression in T cells. The quantification of the percentages of CD8+ T cells and HDAC1+ CD8+ T cells is shown. (F–H) Flow cytometry plots and quantification of the exhaustion markers PD-1 (F), TIM3 (G), and 2B4 (H) on CD8+ T cells from 2-hit model and HDACi-treated mice. (I) Correlation analysis between HDAC1 expression and the exhaustion markers PD-1, TIM3, and 2B4 on CD8+ T cells. Spearman’s correlation coefficients (R) and P values are shown. Data are presented as mean ± SEM. Statistical significance was determined by 1-way ANOVA with Tukey’s multiple-comparison test (B and D), unpaired 2-tailed Student’s t-test (E–H), log-rank test (C), or Spearman’s correlation (I). *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.