人 OX40L-CAR-Treg 靶向活化抗原呈递细胞并控制 T 细胞同种反应性

Regulatory T cells (T regs ) make major contributions to immune homeostasis. Because T reg dysfunction can lead to both allo- and autoimmunity, there is interest in correcting these disorders through T reg adoptive transfer. Two of the central challenges in clinically deploying T reg cellular therapies are ensuring phenotypic stability and maximizing potency.

Here, we describe an approach to address both issues through the creation of OX40 ligand (OX40L)-specific chimeric antigen receptor (CAR)-T regs under the control of a synthetic forkhead box P3 ( FOXP3 ) promoter. The creation of these CAR-T regs enabled selective T reg stimulation by engagement of OX40L, a key activation antigen in alloimmunity, including both graft-versus-host disease and solid organ transplant rejection, and autoimmunity, including rheumatoid arthritis, systemic sclerosis, and systemic lupus erythematosus.

We demonstrated that OX40L-CAR-T regs were robustly activated in the presence of OX40L-expressing cells, leading to up-regulation of T reg suppressive proteins without induction of proinflammatory cytokine production. Compared with control T regs , OX40L-CAR-T regs more potently suppressed alloreactive T cell proliferation in vitro and were directly inhibitory toward activated monocyte-derived dendritic cells (DCs).

We identified trogocytosis as one of the central mechanisms by which these CAR-T regs effectively decrease extracellular display of OX40L, resulting in decreased DC stimulatory capacity. OX40L-CAR-T regs demonstrated an enhanced ability to control xenogeneic graft-versus-host disease compared with control T regs without abolishing the graft-versus-leukemia effect. These results suggest that OX40L-CAR-T regs may have wide applicability as a potent cellular therapy to control both allo- and autoimmune diseases.