Glucocorticoid-induced TNF receptor ligand-dependent B-cell expansion of regulatory T cells as an immune cell therapy strategy.

B-cell-based immune cell therapies represent a potential strategy for restoring immune tolerance by expanding regulatory T cells (Tregs). CD4+Foxp3+ Tregs are essential for maintaining immune homeostasis and represent an attractive therapeutic target. However, clinically established strategies to safely and durably expand endogenous Tregs remain lacking. We previously identified IgDlow/- B cells as a splenic B-cell subset that promotes Treg expansion through a glucocorticoid-induced TNF receptor ligand (GITRL)-dependent mechanism, whereas other B cell populations do not. In B-cell-specific GITRL transgenic mice, Treg numbers are significantly increased, and the severity of experimental autoimmune encephalomyelitis (EAE), a mouse model of multiple sclerosis, is attenuated. To evaluate the translational potential of this pathway as a hematopoietic immune cell therapy, we transplanted wild-type recipients with bone marrow from GITRL transgenic donors. After hematopoietic reconstitution, GITRL expression was selectively increased on B cells. This resulted in the expansion of endogenous Tregs and a corresponding increase in the proportion of Tregs within the CD4+ T-cell compartment, with near-complete suppression of EAE. These findings demonstrate that enhancing GITRL expression within the hematopoietic B-cell compartment provides a tractable strategy for expanding endogenous Tregs and augmenting Treg-mediated immune suppression, establishing a framework for developing B-cell-based immune cell therapies capable of durable immune suppression for inflammatory diseases.