Glucocorticoid-induced TNF Receptor Ligand (GITRL)-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 IgD low B cells (BD L ) 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), the 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. Following hematopoietic reconstitution, GITRL expression was selectively increased on B cells. This resulted in 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.