Increased PD-1 Expression and Altered T Cell Repertoire Diversity Predict Mortality in Patients with Septic Shock: A Preliminary Study

Abstract

Sepsis causes impairment of innate and adaptive immunity by multiple mechanisms, including depletion of immune effector cells and T cell exhaustion. Although lymphocyte dysfunction is associated with increased mortality and potential reactivation of latent viral infection in patients with septic shock, the relation between viral reactivation and lymphocyte dysfunction is obscure. The objectives of this study were 1) to determine the relation of lymphocyte dysfunction to viral reactivation and mortality, and 2) to evaluate recovery of lymphocyte function during septic shock, including T cell receptor (TCR) diversity and the expression of programmed death 1 (PD-1). In 18 patients with septic shock and latent cytomegalovirus (CMV) infection, serial blood samples were obtained on days 1, 3, and 7 after the onset of shock, and immune cell subsets and receptor expression were characterized by flow cytometry. TCR diversity of peripheral blood mononuclear cells was analyzed by Multi-N-plex PCR, and CMV DNA was quantified using a real-time PCR kit. A decrease of TCR diversity and monocyte HLA-DR expression were observed in the early stage of septic shock, while CD4+ T cells displayed an increase of PD-1 expression. Significant lymphopenia persisted for at least 7 days following the onset of septic shock. Normalization of TCR diversity and PD-1 expression was observed by day 7, except in patients who died. CMV reactivation was detected in 3 of the 18 patients during the first week of their ICU stay and all 3 patients died. These changes are consistent with the early stage of immune cell exhaustion and indicate the importance of normal lymphocyte function for recovery from septic shock. Ongoing lymphocyte dysfunction is associated with CMV reactivation and dissemination, as well as with unfavorable outcomes.

Frontline Science: Anti-PD-L1 protects against infection with common bacterial pathogens after burn injury

“…Prior studies among nonburned septic patients show that lymphopenia, upregulation of PD‐1 on T cells and PD‐L1 on monocytes correlate with increased susceptibility to secondary infections, viral reactivation, and increased mortality . We observed a significant decline in lymphocyte numbers in mice with burn wound sepsis.…”

T cell receptor richness in peripheral blood increases after cetuximab therapy and correlates with therapeutic response

“…32 In patients following septic shock, TCR diversity is reduced and normalization of TCR diversity and PD-1 expression was reported to positively correlate with survival. 33 In patients with hepatitis C virus (HCV) infection, Miles and colleagues observed that TCR repertoire diversity is associated with HCV clearance. 34 Hence, TCR diversity is associated with a greater likelihood of a competent immune recognition, which is not restricted to foreign pathogens, with important consequences for cancer immunotherapy.…”

Epidemiology and Immune Pathogenesis of Viral Sepsis

“…This feedback loop would explain why a high degree of viral reactivation (of all viruses) correlates with increased mortality. It is still unclear whether elevated viral loads of herpesviruses following reactivation indeed impairs lymphocyte function or whether it is just a side effect of other kinds of immune suppression already taking place ( 238 ). It has been demonstrated that CMV infection can have an effect on the differentiation of immature lymphocytes into effector CD8 T cells; however, the overall effects this may have on the patient are not well-characterised ( 239 , 240 ).…”