MAIT cell frequency decreased in sepsis-related liver injury, with altered phenotype and function in murine models

Sepsis is a life-threatening condition characterized by increasing global incidence, fundamentally driven by immune dysregulation. The liver, crucial for pathogen clearance and inflammatory modulation during sepsis, frequently exhibits functional impairment. Mucosal-associated invariant T (MAIT) cells bridge innate and adaptive immunity and are integral to antimicrobial defense. Their specific role in sepsis-related liver injury (SRLI) remains unclear. This study aims to elucidate MAIT cell alterations and function in SRLI using clinical cohorts and murine models. The cohort comprised 47 SRLI patients, 37 with non-septic acute liver injury (NSLI), 34 patients with non-associated liver injury in sepsis (NLIS), and 115 healthy controls (HC). Peripheral blood MAIT cells were characterized by flow cytometry for frequency, phenotype, and cytokine production. In vitro experiments assessed effects of bilirubin and cytokines on MAIT cells. A murine SRLI model was established via intraperitoneal lipopolysaccharide (LPS) injection. Liver injury severity, inflammatory cytokines, and histopathology were compared between wild-type and MAIT cell-deficient mice. In the SRLI group, the proportion of peripheral blood MAIT cells was significantly decreased compared to the HC group. Regarding activation (CD69+, CD25+) and exhaustion (PD-1+, Tim-3+) phenotypes, the expression levels of CD69 and PD-1 were markedly upregulated relative to all other groups, while the expression of CD25 and Tim-3 was increased compared to the HC and NSLI groups. In vitro assays indicated that upon stimulation, these MAIT cells preferentially produced IL-17A, TNF-α, and granzyme B, suggesting a bias toward Th17-like differentiation. Elevated concentrations of bilirubin exacerbated both the activation and exhaustion of MAIT cells through a TCR-dependent mechanism. In the septic murine model, MAIT cells deficiency led to more severe liver injury, and higher serum levels of transaminases, bilirubin, and pro-inflammatory cytokines compared to wild-type. In the context of SRLI, peripheral blood MAIT cells exhibit a diminished frequency, functional impairment, and a phenotypic shift toward a Th17-like profile. Among these, bilirubin plays a key role. Ultimately, MAIT cells exert a protective role in sepsis-induced liver injury by suppressing excessive inflammatory responses.