CD8⁺ Regulatory T Cells Induced by Lipopolysaccharide Improve Mouse Endotoxin Shock

Sepsis is a systemic inflammatory disease caused by a bacterial infection that leads to severe mortality, especially in elderly patients, because of an excessive immune response and impaired regulatory functions. Antibiotic treatment is widely accepted as the first-line therapy for sepsis; however, its excessive use has led to the emergence of multidrug-resistant bacteria in patients with sepsis. Therefore, immunotherapy may be effective in treating sepsis. Although CD8⁺ regulatory T cells (Tregs) are known to have immunomodulatory effects in various inflammatory diseases, their role during sepsis remains unclear. In this study, we investigated the role of CD8⁺ Tregs in an LPS-induced endotoxic shock model in young (8–12 wk old) and aged (18–20 mo old) mice. The adoptive transfer of CD8⁺ Tregs into LPS-treated young mice improved the survival rate of LPS-induced endotoxic shock. Moreover, the number of CD8⁺ Tregs in LPS-treated young mice increased through the induction of IL-15 produced by CD11c⁺ cells. In contrast, LPS-treated aged mice showed a reduced induction of CD8⁺ Tregs owing to the limited production of IL-15. Furthermore, CD8⁺ Tregs induced by treatment with the rIL-15/IL-15Ra complex prevented LPS-induced body wight loss and tissue injury in aged mice. In this study, to our knowledge, the induction of CD8⁺ Tregs as novel immunotherapy or adjuvant therapy for endotoxic shock might reduce the uncontrolled immune response and ultimately improve the outcomes of endotoxic shock. ImmunoHorizons, 2023, 7: 353–363.