LAG-3 Represents a Marker of CD4+ T Cells with Regulatory Activity in Patients with Bone Fracture

The lymphocyte activation gene 3 (LAG-3) is a CD4 homolog with binding affinity to MHC class II molecules. It is thought that LAG-3 exerts a bimodal function, such that co-ligation of LAG-3 and CD3 could deliver an inhibitory signal in conventional T cells, whereas, on regulatory T cells, LAG-3 expression could promote their inhibitory function. In this study, we investigated the role of LAG-3 expression on CD4⁺ T cells in patients with long bone fracture. We found that LAG-3⁺ cells represented approximately 13% of peripheral blood CD4⁺ T cells on average. Compared to LAG-3^- CD4⁺ T cells, LAG-3⁺ CD4⁺ T cells presented significantly higher Foxp3 and CTLA-4 expression. Directly ex vivo or with TCR stimulation, LAG-3⁺ CD4⁺ T cells expressed significantly higher levels of IL-10 and TGF-β than LAG-3^- CD4⁺ T cells. Interestingly, blocking the LAG-3-MHC class II interaction actually increased the IL-10 expression by LAG-3⁺ CD4⁺ T cells. The frequency of LAG-3⁺ CD4⁺ T cell was positively correlated with restoration of healthy bone function in long bone fracture patients. These results together suggested that LAG-3 is a marker of CD4⁺ T cells with regulatory function; at the same time, LAG-3 might have limited the full suppressive potential of Treg cells.