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 1

Associations between lymphocyte counts and the CD4/CD8 ratio and prognosis of patients with sepsis.

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Associations between lymphocyte counts and the CD4/CD8 ratio and prognos...
(A) Flowchart showing selection of patients from MIMIC-IV database: 18,220 sepsis admissions were initially identified; after excluding patients without pneumonia (n = 11,624) and those with cancer or autoimmune diseases (n = 4,129), 2,467 patients were included in the final analysis. (B) Restricted cubic spline (RCS) for relationships between initial lymphocyte percentage after admission and 28-day ICU mortality in MIMIC-IV cohort. Solid red line is estimated ORs with 95% CI (red area); vertical dashed line is L-shaped cutoff (9.05%); solid pink curves are fraction of population with different lymphocyte percentages. P < 0.001 for overall association and nonlinearity. (C) Kaplan-Meier survival curves comparing 28-day survival between patients with sepsis with low versus high lymphocyte percentage, stratified by median value at ICU admission. Log-rank test was used to assess differences between groups (P < 0.0001). (D) ROC curves comparing predictive performance of initial lymphocyte percentage (AUC = 0.6469), SOFA score (AUC = 0.6521), and age (AUC = 0.6254) for 28-day mortality in patients with sepsis. AUC with 95% CIs is indicated. AUC comparisons were performed using DeLong’s test. (E) Representative flow cytometry contour plot showing CD4+ and CD8+ T cell subsets gated on live CD3+ lymphocytes from peripheral blood of patients with sepsis. Quadrants indicate proportions of CD4+ (upper left), CD8+ (lower right), double-negative (lower left), and double-positive (upper right) T cell populations. (F) Multivariate linear regression analysis assessing factors associated with SOFA score. Variables included CD4/CD8 ratio, CD8+ T cell proportion, CD4+ T cell proportion, and age. β coefficients with 95% CIs and P values are shown. (G) Mediation analysis illustrating indirect effect of CD8+ T cell proportion on 28-day mortality through SOFA score. Total, direct, and indirect effects (β coefficients) with corresponding P values shown. Indirect effect significance assessed using Bayesian approach (1,000 iterations).