Therapeutic Targeting of Follicular 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. It is unfortunate that no clinical interventions exist for the selective depletion of follicular T cells to alleviate these diseases. We engineered a chimeric antigen receptor (CAR) facilitating the specific targeting of cells with high expression levels of human programmed cell death protein 1 (PD-1), a cardinal feature of follicular T cells. CAR-expressing human natural killer (NK) cells robustly and discriminately eliminated PD-1high follicular human T cells in vitro and in a humanized mouse model of lupus-like disease while sparing B cells and other PD-1low T cell subsets, including regulatory T cells. These results establish a strategy for specific targeting of PD-1high T cells that can be advanced as a clinical tool for the selective depletion of pathogenic follicular T cells or other PD-1high target cells in certain disease states. [Display omitted] TFH exhibit high expression levels of PD-1PD-L1 CAR-expressing NK cells selectively kill TFH but not Treg or memory T cellsKilling of TFH by CAR NK inhibits B cell proliferation and antibody productionThe PD-L1 CAR represents a novel therapeutic tool in TFH-driven diseases Exaggerated follicular helper T cell (TFH) responses promote autoimmunity and other pathologies, yet clinical tools to specifically target TFH are lacking. Reighard et al. describe programmed death-ligand 1 (PD-L1)-based chimeric antigen receptor-expressing human natural killer cells that selectively eliminate human TFHin vitro and in humanized mice based on the high expression of PD-1 by the targeted TFH cells.