Expression of PD-1 on Memory T Lymphocytes Predicts 28-Day Mortality of Patients with Sepsis: A Prospective Observational Study

Background PD-1 is an important immune checkpoint expressed on T lymphocytes and is associated with T-cell function in sepsis. However, the role of PD-1 in naive and memory T-cell responses in sepsis is not well understood. We aimed to determine the expression of PD-1 induced on naive and memory T lymphocytes in patients with sepsis and its association with clinical outcome. Methods A prospective observational study was conducted at a general intensive care unit (ICU). Whole blood samples were collected from patients within 48 h after sepsis diagnosis. PD-1 expression on naive and memory T cells was measured by flow cytometry. The levels of IFN-γ, IL-2 and TNF-α released by memory T cells were also determined. All patients were followed up to 28 days, and 28-day mortality was recorded. Results PD-1 expression showed no difference in naive CD4+ T cells (P=0.617) or naive CD8+ T cells (P=0.079) between survivors (n = 21) and nonsurvivors (n = 9). Increased PD-1 expression on memory CD4+ T cells was found in nonsurvivors (P=0.030) and memory CD8+ T cells (P=0.006) in comparison with survivors. According to the cutoff value of the percentage of PD-1 on memory CD8+ T cells in predicting 28-day mortality of patients with sepsis, patients were divided into two groups. The 28-day mortality rates between the two groups were significantly different (P=0.009). A Kaplan Meier curve was constructed to derive a hazard ratio of 9.33 (95% CI: 2.52–34.60) for the percentage of PD-1 on memory CD8+ T cells regarding 28-day mortality. In addition, the IFN-γ secretion of memory CD4+ T cells (P=0.046) and IL-2 secretion of memory CD8+ T cells (P=0.014) were significantly greater in survivors than nonsurvivors. Conclusion Flow cytometric assessment of PD-1 expression on memory CD8+ T cells identifies patients with poor outcomes during sepsis.

[1]  J. Houtman,et al.  Sepsis leads to lasting changes in phenotype and function of memory CD8 T cells , 2021, eLife.

[2]  M. Yang,et al.  Untargeted Metabolomic Profiling of the Correlation Between Prognosis Differences and PD-1 Expression in Sepsis: A Preliminary Study , 2021, Frontiers in Immunology.

[3]  C. Coopersmith,et al.  The IL-27 receptor regulates TIGIT on memory CD4+ T cells during sepsis , 2021, iScience.

[4]  Dechang Chen,et al.  The Epidemiology of Sepsis in Chinese ICUs: A National Cross-Sectional Survey , 2019, Critical care medicine.

[5]  C. Coopersmith,et al.  Immune checkpoint inhibition in sepsis: a Phase 1b randomized study to evaluate the safety, tolerability, pharmacokinetics, and pharmacodynamics of nivolumab , 2019, Intensive Care Medicine.

[6]  G. Ren,et al.  Different Expression Characteristics of LAG3 and PD-1 in Sepsis and Their Synergistic Effect on T Cell Exhaustion: A New Strategy for Immune Checkpoint Blockade , 2019, Front. Immunol..

[7]  G. Martin,et al.  Increased attrition of memory T cells during sepsis requires 2B4. , 2019, JCI insight.

[8]  C. Coopersmith,et al.  Immune Checkpoint Inhibition in Sepsis: A Phase 1b Randomized, Placebo-Controlled, Single Ascending Dose Study of Antiprogrammed Cell Death-Ligand 1 Antibody (BMS-936559)* , 2019, Critical care medicine.

[9]  C. Coopersmith,et al.  Sepsis erodes CD8+ memory T cell‐protective immunity against an EBV homolog in a 2B4‐dependent manner , 2019, Journal of leukocyte biology.

[10]  R. Hotchkiss,et al.  Restoration of T Cell function in multi-drug resistant bacterial sepsis after interleukin-7, anti-PD-L1, and OX-40 administration , 2018, PloS one.

[11]  V. Badovinac,et al.  Sepsis-Induced T Cell Immunoparalysis: The Ins and Outs of Impaired T Cell Immunity , 2018, The Journal of Immunology.

[12]  C. Coopersmith,et al.  CXCR4 blockade decreases CD4+ T cell exhaustion and improves survival in a murine model of polymicrobial sepsis , 2017, PloS one.

[13]  Susan Gruber,et al.  Incidence and Trends of Sepsis in US Hospitals Using Clinical vs Claims Data, 2009-2014 , 2017, JAMA.

[14]  M. Netea,et al.  The immunopathology of sepsis and potential therapeutic targets , 2017, Nature Reviews Immunology.

[15]  Alan E. Jones,et al.  Surviving Sepsis Campaign: International Guidelines for Management of Sepsis and Septic Shock: 2016 , 2017, Intensive Care Medicine.

[16]  C. Coopersmith,et al.  Attrition of memory CD8 T cells during sepsis requires LFA‐1 , 2016, Journal of leukocyte biology.

[17]  M. Delano,et al.  The immune system's role in sepsis progression, resolution, and long‐term outcome , 2016, Immunological reviews.

[18]  R. Bellomo,et al.  The Third International Consensus Definitions for Sepsis and Septic Shock (Sepsis-3). , 2016, JAMA.

[19]  Henry E. Wang,et al.  Unplanned Readmissions After Hospitalization for Severe Sepsis at Academic Medical Center–Affiliated Hospitals* , 2015, Critical care medicine.

[20]  V. Badovinac,et al.  Polymicrobial Sepsis Increases Susceptibility to Chronic Viral Infection and Exacerbates CD8+ T Cell Exhaustion , 2015, The Journal of Immunology.

[21]  Paul A. Lyons,et al.  T cell exhaustion, costimulation and clinical outcome in autoimmunity and infection , 2015, Nature.

[22]  R. Hotchkiss,et al.  Interleukin-7 and Anti–Programmed Cell Death 1 Antibody Have Differing Effects to Reverse Sepsis-Induced Immunosuppression , 2015, Shock.

[23]  R. Hotchkiss,et al.  Sepsis-induced immunosuppression: from cellular dysfunctions to immunotherapy , 2013, Nature Reviews Immunology.

[24]  Lieping Chen,et al.  Molecular mechanisms of T cell co-stimulation and co-inhibition , 2013, Nature Reviews Immunology.

[25]  V. Badovinac,et al.  Sustained and Incomplete Recovery of Naive CD8+ T Cell Precursors after Sepsis Contributes to Impaired CD8+ T Cell Responses to Infection , 2013, The Journal of Immunology.

[26]  R. Hotchkiss,et al.  A prospective analysis of lymphocyte phenotype and function over the course of acute sepsis , 2012, Critical Care.

[27]  M. Slifka,et al.  Regulation of innate CD8+ T-cell activation mediated by cytokines , 2012, Proceedings of the National Academy of Sciences.

[28]  R. Hotchkiss,et al.  Delayed administration of anti‐PD‐1 antibody reverses immune dysfunction and improves survival during sepsis , 2010, Journal of leukocyte biology.

[29]  A. Lanfranco,et al.  CTLA-4 and PD-1 Receptors Inhibit T-Cell Activation by Distinct Mechanisms , 2004, Molecular and Cellular Biology.

[30]  R. Hotchkiss,et al.  Sepsis-Induced Apoptosis Causes Progressive Profound Depletion of B and CD4+ T Lymphocytes in Humans1 , 2001, The Journal of Immunology.