Overexpression of GITRL by B cell IgD low (BDL) B cells is a therapeutic strategy to increase endogenous CD4+Foxp3+ T regulatory cells for the treatment of autoimmunity

Abstract

Autoimmune diseases, such as multiple sclerosis (MS), are often chronic with no cures. An underlying commonality of autoimmune diseases is immune-mediated inflammation. Control of inflammation is achieved by steroids and disease-modifying therapies, which can result in severe side-effects. CD4+Foxp3+ T regulatory cells (Treg), are essential to controlling autoimmune responses and are considered a strong therapeutic target with minimal side effects. To that end, we leveraged our identification of B cell IgD low (BDL) B cells that control Treg homeostatic levels in the mouse spleen in a GITRL-dependent manner to demonstrate that overexpression of GITRL by BDL using a B cell-specific GITRL transgene (tg) was sufficient to increase endogenous Treg numbers and attenuate the disease severity of experimental autoimmune encephalomyelitis (EAE), the mouse model of MS. To determine whether increased GITRL expression by BDL could be a therapeutic strategy, WT mice were transplanted with bone marrow from GITRLtg mice. After reconstitution, GITRL expression was increased on BDL, Treg numbers were significantly elevated, and EAE was dramatically attenuated. These cumulative data further demonstrate that GITRL is a functional receptor on BDL and its overexpression in B cells is a therapeutic strategy to increase endogenous Treg numbers for treating autoimmunity.