Notch signaling pathway regulates T cell dysfunction in septic patients

Abstract

Sepsis disrupts innate and adaptive immune response, and immune disorders may also impact clinical course of sepsis. Notch signaling pathway plays a vital role in T cell modulation and differentiation. The aim of current study was to investigate the immunoregulatory function of Notch signaling pathway to T cells in patients with sepsis and septic shock. Twenty-seven sepsis patients, twenty-five septic shock patients, and twenty-one normal controls (NCs) were enrolled. Notch receptors mRNA levels were semi-quantified by real-time PCR. The absolute numbers of CD3⁺, CD4⁺, and CD8⁺ T cells were measured by flow cytometry. Key transcriptional factors of CD4⁺ T cells, cytotoxic molecules in CD8⁺ T cells, and cytotoxicity of CD8⁺ T cells were investigated. The regulatory activities of Notch signaling inhibition by γ-secretase inhibitor (GSI) on purified CD4⁺ and CD8⁺ T cells from sepsis and septic shock patients were also assessed. Notch1 mRNA relative level was significantly elevated in sepsis and septic shock patients when compared with NCs. CD4⁺ and CD8⁺ T cells were dysfunctional in sepsis and septic shock, which presented as decreased cell accounts, down-regulation of Th1/Th17 transcriptional factors and cytotoxic molecules (perforin, granzyme B, and FasL), and reduced cytotoxicity of CD8⁺ T cells. Notch signaling inhibition by GSI increased Th1 and Th17 differentiation of CD4⁺ T cells. Moreover, GSI stimulation not only promoted perforin, granzyme B, and FasL mRNA expression in CD8⁺ T cells, but also elevated CD8⁺ T cell-induced target cell death and IFN-γ/TNF-α production in sepsis and septic shock. The current data suggest that Notch signaling pathway contributes to T cell dysfunction and limited immune response in sepsis.

Keywords: Immunoregulation; Notch signaling; Sepsis; T cells.