Immune Checkpoint Molecules as Biomarkers of Bone Infection and Clinical Outcome.

prosthetic joint infections (PJIs) are broadly considered incurable, and clinical diagnostics that guide conservative vs. aggressive surgical treatments don't exist. Multi-omics studies in a humanized NSG-SGM3 BLT mouse model demonstrate human T cells: 1) are remarkably heterogenous in gene expression and numbers, and 2) exist as a mixed population of activated, progenitor-exhausted, and terminally-exhausted Th1/Th17 cells with increased expression of immune checkpoint proteins (LAG3, TIM-3). Importantly, these proteins are upregulated in the serum and the bone marrow of PJI patients. A multiparametric nomogram combining high serum immune checkpoint protein levels with low proinflammatory cytokine levels (IFN-γ, IL-2, TNF-α, IL-17) revealed that TIM-3 was highly predictive of adverse disease outcomes (AUC=0.89). Hence, T cell impairment in the form of immune checkpoint expression and exhaustion could be a functional biomarker for PJI disease outcome, and blockade of checkpoint proteins could potentially improve outcomes following surgery.