T CELL EXHAUSTION IN BONE INFECTION AND ADVERSE CLINICAL OUTCOME

Bone infections remain among the most challenging complications in orthopaedic surgery, often leading to recurrence, repeated procedures, prolonged antibiotic treatment, and poor patient outcomes. However, the biological factors that distinguish patients who recover from those who progress to chronic or complicated infection remain poorly defined. We sought to identify immune mechanisms linked to persistence and clinical outcome, focusing on human T cell responses within the infected bone marrow microenvironment. Using clinically relevant humanized mouse models and patient-derived samples, we found marked remodeling of the human CD4 T cell compartment during Staphylococcus aureus bone infection. Human CD4 T cells accumulated at infected sites as heterogeneous Th1 and Th17 populations that progressively acquired features of functional exhaustion, including elevated TIM-3 and LAG-3 expression, reduced proliferation, and impaired cytokine production. Importantly, these immune signatures were also detectable in patient serum, where increased immune checkpoint proteins, particularly TIM-3, strongly predicted adverse clinical outcomes. These findings identify T cell dysfunction as a key feature of chronic bone infection and suggest that immune checkpoint pathways may serve as clinically useful biomarkers for prognosis and patient stratification. More broadly, this work reframes chronic osteomyelitis as an immune failure state and highlights new opportunities for improved diagnostics and immune-directed treatment strategies.