Myeloid-derived suppressor cell inhibits T-cell-based defense against Klebsiella pneumoniae infection via IDO1 production.

Summary

In hypervirulent K. pneumoniae bacteremia, MDSCs suppress T-cell proliferation via an IDO1-driven tryptophan–kynurenine pathway, causing lymphopenia and weakened antibacterial responses. Genetic deletion or pharmacologic inhibition of IDO1 restored T-cell responses, nominating IDO1 as an immunotherapeutic target.

Key Findings

• hvKp infection induces lymphopenia via impaired T-cell proliferation and apoptosis.
• MDSCs infiltrate infected lungs and suppress T-cell proliferation through IDO1-driven tryptophan metabolism.
• L-kynurenine inhibits T-cell proliferation and induces apoptosis ex vivo; IDO1 knockout or 1-MT inhibition enhances T-cell responses in vivo.

Clinical Implications

Adjunctive IDO1 inhibition could enhance T-cell immunity in severe Gram-negative sepsis, particularly hvKp. Monitoring lymphopenia and tryptophan–kynurenine markers may guide host-directed therapies.

Limitations

• Preclinical mouse model; clinical validation in humans is needed.
• Specificity and translational dosing of 1-MT may limit direct clinical applicability.

Future Directions

Assess IDO1 inhibitors and MDSC-targeted strategies in clinical sepsis; define biomarkers (kynurenine/tryptophan ratios, MDSC signatures) to stratify patients for host-directed therapy.