{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,3]],"date-time":"2026-06-03T04:04:12Z","timestamp":1780459452544,"version":"3.54.1"},"reference-count":68,"publisher":"MDPI AG","issue":"6","license":[{"start":{"date-parts":[[2026,5,23]],"date-time":"2026-05-23T00:00:00Z","timestamp":1779494400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Ministry of Education and Science of Russia","award":["FGWS-2025-0008"],"award-info":[{"award-number":["FGWS-2025-0008"]}]},{"name":"Ministry of Education and Science of Russia","award":["125091010190-9"],"award-info":[{"award-number":["125091010190-9"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JPM"],"abstract":"<jats:p>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\u2014a proposed marker of adaptive homeostatic resilience\u2014is 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\u2013Q4) based on the slope of their TREC trajectories. \u201cQualifying variants\u201d (QVs) were defined using strict rarity (gnomAD allele frequency \u2264 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 &lt; 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 \u201chousekeeping\u201d 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\u2019s ability to maintain T-cell homeostasis during critical illness is influenced by their underlying genetic buffering capacity. We propose a hypothetical \u201ctwo-hit\u201d framework where physiological stress unmasks pre-existing fragilities in core homeostatic pathways\u2014potentially reflecting a state of functional haploinsufficiency under extreme proliferative demand\u2014leading 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.<\/jats:p>","DOI":"10.3390\/jpm16060278","type":"journal-article","created":{"date-parts":[[2026,5,25]],"date-time":"2026-05-25T01:45:08Z","timestamp":1779673508000},"page":"278","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Genetic Determinants of T-Cell Homeostasis in Critical Illness: An Exploratory Analysis of Immune Gene Variants and TREC Dynamics"],"prefix":"10.3390","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-1361-6085","authenticated-orcid":false,"given":"Alesya S.","family":"Gracheva","sequence":"first","affiliation":[{"name":"Vavilov Institute of General Genetics, Russian Academy of Sciences, 119333 Moscow, Russia"},{"name":"Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology, 107031 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3051-6756","authenticated-orcid":false,"given":"Darya A.","family":"Kashatnikova","sequence":"additional","affiliation":[{"name":"Vavilov Institute of General Genetics, Russian Academy of Sciences, 119333 Moscow, Russia"},{"name":"Lopukhin Federal Research and Clinical Center of Physical-Chemical Medicine, Federal Medical Biological Agency, 119435 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8980-4851","authenticated-orcid":false,"given":"Maryam B.","family":"Khadzhieva","sequence":"additional","affiliation":[{"name":"Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology, 107031 Moscow, Russia"},{"name":"National Research Center of Pediatric Hematology, Oncology and Immunology, 117997 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4873-8007","authenticated-orcid":false,"given":"Vladislav E.","family":"Zakharchenko","sequence":"additional","affiliation":[{"name":"Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology, 107031 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tatyana N.","family":"Krylova","sequence":"additional","affiliation":[{"name":"Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology, 107031 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5930-0118","authenticated-orcid":false,"given":"Artem N.","family":"Kuzovlev","sequence":"additional","affiliation":[{"name":"Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology, 107031 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9671-335X","authenticated-orcid":false,"given":"Lyubov E.","family":"Salnikova","sequence":"additional","affiliation":[{"name":"Vavilov Institute of General Genetics, Russian Academy of Sciences, 119333 Moscow, Russia"},{"name":"Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology, 107031 Moscow, Russia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,5,23]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"10186","DOI":"10.1038\/s41598-018-28409-7","article-title":"Innate and Adaptive Immune Dysregulation in Critically Ill ICU Patients","volume":"8","author":"Duggal","year":"2018","journal-title":"Sci. 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