Therapeutic Targeting of Follicular Helper T Cells with Chimeric Antigen Receptor-Expressing Natural Killer Cells

Follicular helper T cells (TFH) are critical for vaccine and infection elicitation of long-lived humoral immunity, but exaggerated TFH responses can promote autoimmunity and other pathologies. Unfortunately, no clinical interventions are currently available for selective depletion of TFH cells to alleviate these disease conditions. We engineered a novel chimeric antigen receptor (CAR) that facilitates specific targeting of cells highly expressing human programmed cell death protein 1 (PD-1), a cardinal feature of TFH cells. CAR-expressing natural killer (NK) cells robustly degranulate in response to PD-1, resulting in discriminatory elimination of human tonsil TFH cells while sparing other T and B-cell subsets. Given that CAR NK cells are emerging as a safe and effective alternative to CAR T cells in cancer immunotherapy, our results suggest a new, clinically-translatable application of CAR NK cells for selective depletion of pathogenic TFH cells in specific disease states.