Metabolic and Functional Study of γδ T Cells in Critically Ill Patients

Condition(s) studied

Study summary

This prospective observational cohort study investigates the subset-specific metabolic adaptation and functional remodeling of cytotoxic γδ T cells in critically ill patients with and without sepsis. As a bridge between innate and adaptive immunity, γδ T cells contribute to early antimicrobial defense; however, their cytotoxic function and its metabolic regulation in sepsis remain incompletely understood. Our preliminary single-cell transcriptomic analysis revealed altered expression of cytotoxicity-associated genes (GZMB, PRF1, and GNLY) and mitochondrial oxidative phosphorylation (OXPHOS) pathway genes in cytotoxic γδ T cells from patients with sepsis. In particular, COX6C expression correlated with cytotoxic effector gene expression. Across healthy volunteers, critically ill non-septic patients, and critically ill septic patients, we will integrate flow cytometry, mitochondrial function assays, and functional validation experiments to characterize circulating cytotoxic γδ T-cell abundance and function and examine the contribution of COX6C to mitochondrial dysfunction and impaired cytotoxicity.

To investigate the relationship between systemic tryptophan metabolism and these cellular abnormalities, targeted tryptophan-pathway metabolomics using liquid chromatography-tandem mass spectrometry (LC-MS/MS) will quantify kynurenic acid (KYNA), tryptophan, kynurenine, and related metabolites in paired peripheral blood and fecal samples. Patients with sepsis will be stratified into older (≥65 years) and non-older (\<65 years) groups and compared with age-matched healthy volunteers, with critically ill non-septic patients providing an additional disease control group. Metabolite concentrations and pathway-related ratios will be analyzed in relation to cytotoxic γδ T-cell abundance, cytotoxic function, mitochondrial OXPHOS, and COX6C expression, accounting for renal function, disease severity, antibiotic exposure, and nutritional support. These analyses will assess whether age-associated alterations in tryptophan metabolism, particularly KYNA, are associated with cytotoxic γδ T-cell dysfunction and identify candidate metabolic mechanisms for subsequent validation.

Eligibility

Primary outcome measure(s)

• Change in the Proportion of Cytotoxic γδT Cells (TCRγδ⁺GZMB⁺PRF1⁺GNLY⁺) Among Total γδT Cells — Within day 2 post-ICU admission
  Flow cytometric quantification of the frequency of Cytotoxic γδT cells, defined as TCRγδ⁺GZMB⁺PRF1⁺GNLY⁺ cells, as a percentage of total γδT cells (TCRγδ⁺) in peripheral blood. This subset represents the cytotoxic effector population critical for early anti-infection defense.

Trial sites (1)

More Union Hospital, Tongji Medical College, Huazhong University of Science and Technology trials in China

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