Sepsis produces a dysregulated host response to infection with simultaneous hyperinflammation and immunosuppression. Alterations in adaptive immunity, particularly loss of circulating T lymphocytes, are repeatedly associated with worse outcomes. The interferon‑γ‑inducible chemokine CXCL10 (IP‑10) mediates CXCR3‑dependent T cell trafficking and has been implicated in immune activation, T cell redistribution/exhaustion, and organ injury in sepsis. Genetic variation in CXCL10 may contribute to inter‑individual differences in CXCL10 expression and function. The 3′ untranslated region SNP rs8878 has prior associations with altered CXCL10 expression in inflammatory disorders and was therefore assessed here as a candidate variant for effects on T cell homeostasis and outcome in sepsis.
This prospective multicenter observational study analyzed patients enrolled in the SepsisDataNet.NRW cohort. A total of 278 patients with sepsis were genotyped for CXCL10 rs8878. Patients were recruited consecutively between March 1, 2018, and May 31, 2022. Inclusion required age ≥18 years and fulfillment of Sepsis‑3 criteria. Blood for DNA, RNA, serum, and flow cytometry was collected within 36 hours of sepsis diagnosis. The study was approved by the Ethics Committee of the Medical Faculty of Ruhr‑University Bochum, and written informed consent was obtained from patients or legal guardians.
DNA was isolated from EDTA blood and rs8878 genotyping performed using a TaqMan SNP assay on standard real‑time PCR instrumentation. Whole‑blood RNA was extracted from Tempus tubes and reverse‑transcribed; CXCL10 expression was quantified by qPCR relative to ACTB. CXCL10 serum concentrations were measured by ELISA. Plasma proteomics used data processed with DIA‑NN and log2‑normalized intensities; a matched subcohort was generated by propensity score matching (1:2) to compare AA genotype carriers with GG/AG controls while balancing sex and SOFA score.
Fresh EDTA blood samples were stained and analyzed by flow cytometry (CytoFlex). In the subset of patients with FACS data (n=145), circulating immune cell counts including total T cells, CD4+ and CD8+ populations were determined using standard antibody panels and acquisition protocols described in the methods.
Carriers of the rs8878 AA genotype exhibited higher circulating T cell counts and improved 30‑day survival compared with G‑allele carriers (AG/GG). Higher total and CD8+ T cell counts measured on day 1 were significantly associated with better 30‑day survival across the cohort. Among non‑survivors, AA genotype carriers showed elevated CXCL10 mRNA expression in whole blood, suggesting genotype‑dependent regulation of CXCL10 under conditions of fatal disease progression. Routine clinical parameters and baseline characteristics were generally similar between genotype groups, with cohort tables presenting demographic and clinical descriptors.
CXCL10 concentrations on day 1 correlated positively with multiple inflammatory cytokines measured in plasma, including IL‑6, IL‑8, IL‑10, IL‑18, MCP‑1, IFN‑γ, and IFN‑α2. Conversely, CXCL10 levels were inversely correlated with total circulating T cell counts. These relationships support a link between elevated CXCL10, systemic inflammation, and T cell depletion in sepsis.
A proteomics comparison was performed in a cohort of 252 patients, including 30 AA genotype carriers. Propensity score matching (1:2) for sex and SOFA score produced matched comparison groups. After batch normalization, quality control, and multiple testing correction, no significant differences in plasma protein intensities between AA and GG/AG genotype groups were observed in the analyzed dataset.
The data indicate that the CXCL10 rs8878 variant is associated with T cell dynamics and 30‑day survival in sepsis: the AA genotype is linked to preserved circulating T cell counts and improved survival, while increased CXCL10 expression among AA non‑survivors suggests a context‑dependent role of CXCL10 in inflammation‑driven immune dysregulation. Correlations between CXCL10 and multiple inflammatory cytokines, together with inverse relationships to T cell counts, are consistent with CXCL10 functioning at the interface of systemic inflammation and adaptive immune perturbation. These findings nominate CXCL10 genetics and expression as potential biomarkers for risk stratification and as a candidate axis for immunomodulatory interventions in sepsis.
The source reports associations but does not establish mechanistic causality. Details on effect sizes, specific cutoff values for cell counts predicting survival, or interventional implications beyond candidate status were not reported. Proteomics did not reveal genotype‑specific plasma protein differences after matching and correction, but sample sizes and detection limits could influence sensitivity. Further studies are needed to validate findings in independent cohorts, to clarify mechanistic links between rs8878, CXCL10 regulation, and T cell fate, and to explore whether CXCL10‑directed therapies could alter clinical outcomes.