Lead pollution is global, billions of people are chronically exposed to lead. Biological thiols are nature sequesters of lead. Human immune system is highly vulnerable to lead, unfortunately the underlying mechanism remains unknown. Using mass cytometry and mass spectrometry, we systematically identified lead targets in immune cells from mice model of chronic lead exposure. We found CD4+ T and neutrophil are most vulnerable to lead, respectively due to low thiol and high glutathione metabolism. Specifically, in CD4+ T, lack of thiol renders severe damage of ribosome by lead, which we successfully rescued using thiol drugs. In neutrophil, robust glutathione metabolism accumulates lead, which can be passed on to proteins of higher binding affinity. Among these proteins, our evidences suggest lead suppresses immune activation through PKC-like, PE/DAG-binding domain on RAF1 and PKCs. Overall, it clarified the mechanisms of toxicity in immune cells upon chronic lead exposure, which provides valuable information for medical care and public health.