Restoration of Mucosa-Associated Invariant T-Cell Function in Healthcare-Associated Bacterial Infections Supports Recovery of Carbapenem Efficacy Against Resistant Bacteria Ex Vivo.

Abstract

Antimicrobial resistance (AMR) is a major challenge in healthcare-associated infections (HAIs), especially in immunocompromised individuals and those with comorbidities, who often have an impaired mucosa-associated invariant T (MAIT) cell pool. MAIT cells are innate-like T cells enriched in mucosal tissues with potent antimicrobial activity. Restoring their function may offer a host-directed strategy against drug-resistant pathogens. We evaluated how cognate antigen in combination with cytokines modulates MAIT cell cytotoxicity and enhances carbapenem activity. MAIT cell cytolytic protein expression, cytotoxicity, and effector function were measured after stimulation. Secretomes from activated MAIT cells were tested against engineered Escherichia coli expressing clinically relevant carbapenemases. Under optimal conditions, MAIT cells upregulated antimicrobial cytolytic proteins and efficiently killed antigen-pulsed target cells. Interleukin (IL)-15 or IL-2 plus IL-7 most effectively promoted polyfunctional cytotoxic responses. Secretomes from cytokine-stimulated MAIT cells restored imipenem activity against Escherichia coli expressing blaNDM-1, blaKPC-2, and blaOXA-48, reducing metabolic activity, viability, and growth. Notably, IL-2 plus IL-7 enabled expansion and functional restoration of MAIT cells from HAI patients with diminished baseline numbers and responses. Tailored antigen and cytokine stimulation reinvigorates MAIT cell effector function and augments carbapenem efficacy, supporting MAIT cell-based host-directed adjunct strategies against AMR in vulnerable patients.