Persistent IL-17 Cytokine Patterns and Th17 Expansion Characterize Chronic Critical Illness after Severe Trauma 2310055

Abstract Introduction Severe trauma triggers a dynamic disturbance of immune function that can progress from early hyperinflammation to prolonged dysregulation, increasing patient vulnerability to infection and chronic critical illness (CCI). While underlying mechanisms that drive vulnerability in CCI remains unclear, we hypothesize that intrinsic T-cell functionality is impaired. Methods To identify immune features linked to different post-injury clinical trajectories, we prospectively evaluated severely injured trauma patients and categorized them as rapid recovery (RR), intermediate (IM), or CCI by day 14 of ICU admission. Results CCI patients developed infections earlier and more frequently than RR or IM patients, with nearly one-third experiencing their first infection (primarily pneumonia) within 4 days of ICU admission and >80% did so within 8 days. Immune profiling showed trauma-associated alterations across all groups, including neutrophilia and early T-cell lymphopenia. However, CCI patients exhibited a distinct immunophenotype characterized by elevated neutrophil counts, preserved inducible IFNγ production, and a selective expansion of CD4+ Th17 cells. Functional assays revealed sustained or amplified T-cell cytokine responses in CCI patients, including persistent IFNγ and IL-17A production. Plasma cytokine analysis further demonstrated prolonged elevation of IL-17A, IL-17C, IFNγ, and IL-10, indicating a mixed but enduring pro- and anti-inflammatory state. Conclusion These findings suggest CCI after trauma is not driven by intrinsic T-cell impairment but by an IL-17-skewed immune program coupled with ineffective pathogen control. The persistent Th17/neutrophil axis may contribute to heightened infection risk and progression to CCI, highlighting dysregulated IL-17-mediated inflammatory circuits as a potential mechanism of ongoing immune dysfunction following severe trauma. Funding Source National Institutes of Health: GM142481 Topic Categories Translational and Interventional Immunology (TI)