Genetic Determinants of T-Cell Homeostasis in Critical Illness: An Exploratory Analysis of Immune Gene Variants and TREC Dynamics

Background: Chronic critical illness (CCI) following acute brain injury involves persistent immune dysfunction, yet its genetic determinants remain unclear. We investigated whether the rate of T-cell receptor excision circle (TREC) depletion—a proposed marker of adaptive homeostatic resilience—is associated with the burden of rare damaging genetic variants. Methods: Whole-exome sequencing (WES) was performed on a cohort of 84 patients (64 with traumatic brain injury, 20 with stroke). In a longitudinal sub-cohort (n = 27), patients were stratified into quartiles (Q1–Q4) based on the slope of their TREC trajectories. ‘Qualifying variants’ (QVs) were defined using strict rarity (gnomAD allele frequency ≤ 0.001) and pathogenicity criteria. Gene-level burden (collapsing) analysis and permutation-based statistical testing (10,000 iterations) were employed to evaluate genetic enrichment in the extreme quartiles. Results: While baseline TREC levels were strictly age dependent (p < 0.0001), the rate of change (TREC slope) was age independent. Rapid TREC decline (Q1) correlated with significantly higher final SOFA scores (p = 0.001) and neutrophil-to-lymphocyte ratios (p = 0.020). Rare variant burden analysis revealed that Q1 patients were significantly more likely to harbor QVs in immune-related genes compared to the Q4 recovery group (odds ratio = 8.25; permutation p = 0.016). Patients with rapid decline were enriched for QVs in putative core “housekeeping” pathways essential for T-cell maintenance and DNA repair (e.g., ERCC3, FANCM), whereas variants in recovering patients were restricted to peripheral effector or structural pathways. Conclusions: Our findings suggest, as a conceptual framework, that an individual’s ability to maintain T-cell homeostasis during critical illness is influenced by their underlying genetic buffering capacity. We propose a hypothetical “two-hit” framework where physiological stress unmasks pre-existing fragilities in core homeostatic pathways—potentially reflecting a state of functional haploinsufficiency under extreme proliferative demand—leading to accelerated immune exhaustion. These results position the TREC slope as a dynamic, age-independent biomarker of genomic resilience in the ICU. All findings are exploratory and hypothesis generating.