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

Abstract

Follicular helper T cells (T_FH) are critical for vaccine and infection elicitation of long-lived humoral immunity, but exaggerated T_FH 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-1^high follicular human T cells <i>in vitro</i> and in a humanized mouse model of lupus-like disease while sparing B cells and other PD-1^low T cell subsets, including regulatory T cells. These results establish a strategy for specific targeting of PD-1^high T cells that can be advanced as a clinical tool for the selective depletion of pathogenic follicular T cells or other PD-1^high target cells in certain disease states.