Role of the TNF-family cytokine TL1A and its receptor DR3 in systemic autoimmunity and glomerulonephritis

Abstract

Abstract DR3 (Tnsfrsf25) is a death domain-containing tumor necrosis factor receptor found primarily on activated T cells and innate lymphocytes. Interaction with its ligand the TNF-family cytokine TL1A plays critical roles in diverse autoimmune disease models in facilitating T cell accumulation at the site of inflammation while the systemic response was unaffected. To determine whether DR3 could play a role in systemic autoimmunity, we studied the role of DR3 in the MLR/lpr mouse model of lupus. Lpr mice have a mutation in the TNF family receptor Fas (CD95, Tnfrsf6) that impair its expression, causing a systemic autoimmune disease that mimics systemic lupus erythematosus (SLE) observed in humans. DR3 deficient lpr mice developed identical degrees of lymphadenopathy, splenomegaly compared to control littermates. Accumulation of autoantibodies was also not dependent on DR3. However, DR3 deficiency significantly protected MRL/lpr mice from IgG and C3 glomerular immune complex deposition and DR3 deficient kidneys had decreased medullary T cell accumulation, decreased periglomerular and medullary macrophage infiltrates, reduced proteinuria and reduced renal pathology. In addition, DR3-deficient CD4+ T cell transfer in a chronic graft-versus-host disease (GVHD) model showed similar levels of autoantibodies and immunoglobulin class switching than with wild-type CD4+ T cells but decreased proteinuria and reduced renal pathology. These findings show that DR3 specifically promotes renal pathology in the MRL/lpr mouse model of lupus nephritis and in chronic GVHD without affecting systemic autoimmunity. Blockade of TL1A-DR3 interactions may be a novel strategy to counter nephritis and other organ damage in human SLE.