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CD40 and CD80/86 Act Synergistically to Regulate Inflammation and Mortality in Polymicrobial Sepsis

¹ Division of Pulmonary Critical Care, New York University School of Medicine, New York, New York; and ² Division of Pulmonary Critical Care, Oregon Health and Science University, Portland, Oregon

Correspondence and requests for reprints should be addressed to Jeffrey A. Gold, M.D., Oregon Health and Science University, Division of Pulmonary and Critical Care, Mail Code UHN67, 3181 SW Sam Jackson Park Road, Portland, OR 97239. E-mail: goldje{at}ohsu.edu

Rationale: Costimulatory molecules, including the CD40–CD154 and CD80/86–CD28 dyads, play a prominent role in regulating inflammation in the adaptive immune response. Studies from our group and others suggest a potentially important role for these costimulatory cascades in innate immunity as well.

Objectives: To determine the role of CD80/86 alone and in combination with CD40 in lethal polymicrobial sepsis in mice and humans.

Methods: The murine cecal ligation and puncture (CLP) model was used to determine the role of CD80/86 alone and in combination with CD40 using wild-type mice, CD80/86^–/– mice, and novel CD40/80/86^–/– mice. Expression of cell-bound and soluble costimulatory molecules was assessed in humans via ELISA and flow cytometry.

Measurements and Main Results: Lethal CLP was associated with up-regulation of CD40 and CD80/86 and their respective ligands CD28 and CD154 on innate effector cells. Blockade or deletion of CD80/86 attenuated mortality and inflammatory cytokine production during CLP. CD40/80/86^–/– mice exhibited further reductions in mortality, lung injury, and inflammatory cytokine production compared with CD80/86^–/– mice. Finally, humans with sepsis had increased monocyte expression of CD40 and CD80 compared with healthy control subjects; with higher levels in subjects requiring vasopressor support. Levels of soluble CD28 and CD154 were significantly higher in patients who died compared with those who lived.

Conclusions: These data demonstrate a central role for CD40 and CD80/86 in the innate immune response and suggest that combined inhibition of CD40 and CD80/86 may improve mortality in sepsis. Expression of costimulatory molecules may serve as biomarkers for outcome in septic patients.

Key Words: costimulation • innate immunity • sepsis

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject At present, there is little known about the role of costimulatory molecules in regulating inflammation in severe sepsis. What This Study Adds to This Field This study suggests that costimulatory molecules have an important role in regulating inflammation and mortality in lethal sepsis, and provides support for a paradigm in which costimulatory molecules act synergistically to regulate severe inflammatory responses to bacterial infection.