GITRL expressed by regulatory B cells is the key to expanding T-regulatory cells to the level required to ameliorate autoimmunity

Abstract

Abstract CD4+Foxp3+ T regulatory cells (Treg) are well characterized for their role in controlling autoimmunity. We have previously shown that mice deficient in B cells (μMT) have significantly reduced Treg and cannot recover from the mouse model of multiple sclerosis, experimental autoimmune encephalomyelitis (EAE), demonstrating a regulatory role for B cells in immune tolerance. Using B cell depletion strategies and phenotyping, we discovered B cell IgD Low (BDL) regulatory B cells that when adoptively transferred into μMT mice increased Treg numbers and drove EAE recovery. BDL activity was found to be dependent upon glucocorticoid-induced tumor necrosis factor receptor-related protein ligand (GITRL), which engages GITR on Treg inducing their proliferation. To investigate whether BDL activity could be enhanced, B cell-specific GITRL transgenic (tg) mice were obtained. These mice had three-fold more Treg than WT mice consistent with attenuated EAE. Adoptive transfer of GITRLtg BDL into μMT mice did not increase Treg numbers nor reduce EAE severity as compared to WT BDL. Here we posit that sustaining elevated Treg numbers is required to ameliorate EAE to clinical scores below that of WT, as seen in GITRLtg mice. This holds translational implications for many autoimmune diseases for which Treg cell therapies have been proposed. New approaches must be examined to not only increase Treg in autoimmune patients, but also to retain these levels over longer periods of time.