Diverse NKT cells regulate early inflammation and neurological outcomes after cardiac arrest and resuscitation
Neurological injury drives most deaths and morbidity among patients hospitalized for out-of-hospital cardiac arrest (OHCA). Despite its clinical importance, there are no effective pharmacological therapies targeting post-cardiac arrest (CA) neurological injury. Here we analyzed circulating immune cells from a large OHCA patient cohort, finding that lymphopenia independently associated with poor neurological outcomes. Single cell RNA-sequencing of immune cells showed that T cells with features of both innate T cells and natural killer (NK) cells were increased in patients with favorable neurological outcomes. We more specifically identified an early increase in circulating diverse NKT cells (dNKT) in a separate cohort of OHCA patients with good neurological outcomes. These cells harbored a diverse T cell receptor repertoire but were consistently specific for sulfatide antigen. In mice, we found that sulfatide-specific dNKT cells trafficked to the brain after CA and resuscitation. In the brains of mice lacking NKT cells (Cd1d-/-), we observed increased inflammatory chemokine and cytokine expression and accumulation of macrophages when compared with wild-type mice. Cd1d-/- mice also had increased neuronal injury, neurological dysfunction, and worse mortality after CA. To therapeutically enhance dNKT cell activity, we treated mice with sulfatide lipid after CA, showing that it improved neurological function. Together, these data show that sulfatide-specific dNKT cells are associated with good neurological outcomes after clinical OHCA and are neuroprotective in mice after CA. Strategies to enhance the number or function of dNKT cells may thus represent a treatment approach for CA. Overall design: Cardiac arrest (CA) was induced in WT or CD1d KO ten-week-old male mice on C57BL/6J with 80 ug potassium chloride per g body weight, after 8 minutes of arrest, epinephrine and ches compressions were applied for resucitation. Nuclei was extracted from hippocampus region 24 hr post CA.