CXCL10 rs8878 identifies a genotype-associated immune phenotype linked to T-lymphocyte preservation and survival in sepsis

Background: Sepsis is characterized by a dysregulated host response to infection, leading to concurrent hyperinflammation and immunosuppression, including profound alterations in T lymphocyte homeostasis. The chemokine CXCL10, an interferon-γ-inducible mediator of T cell trafficking, has been implicated in immune activation and tissue injury. However, it remains unclear whether genetic variation in CXCL10 contributes to T cell dysregulation and clinical outcomes in sepsis. Methods: In a prospective cohort of septic patients (n=278), we analyzed CXCL10 rs8878 genotypes, circulating immune cell counts, cytokine concentrations, and CXCL10 protein and mRNA expression in whole blood. Associations between genotype, immune parameters, plasma proteomics and 30-day survival were assessed using group comparisons and Kaplan-Meier analyses. Correlation analyses were performed to evaluate relationships between CXCL10 concentrations, cytokines, and clinical parameters. Results: T cell counts were significantly associated with improved survival. Among non-survivors, AA-genotype carriers showed increased CXCL10 mRNA expression, indicating genotype-dependent regulation of CXCL10 expression under conditions of fatal disease progression. CXCL10 concentrations on day 1 were positively correlated with multiple inflammatory cytokines, including IL-6, IL-8, IL-10, IL-18, MCP-1, IFN-γ, and interferon-α2, and inversely correlated with total T cell counts, supporting a link between CXCL10, systemic inflammation, and T cell depletion. No significant associations were observed between CXCL10 genotype and plasma proteomics and routine clinical parameters. Conclusion: The CXCL10 rs8878 genotype is associated with T cell dynamics and 30-day survival in sepsis, suggesting a genotype-dependent modulation of the adaptive immune response. While the AA genotype is linked to preserved T cell counts and improved outcomes, increased CXCL10 expression in non-survivors points to a context-dependent role in inflammation-driven immune dysregulation. These findings identify CXCL10 as a potential biomarker for risk stratification and a candidate target for immunomodulatory therapies in sepsis.