Micromanaging lupus nephritis: miR17-92 modulates TFH development and regulatory T cell activity

Abstract

Abstract T follicular helper (TFH) cell provide crucial growth signals to germinal center (GC) B cells supporting antibody production. Tight control of TFH numbers maintains self-tolerance. Regulatory T (Treg) cells play a critical role in maintaining self-tolerance and controlling the magnitude of physiologic immune response. The Treg transcription factor forkhead box P3 (Foxp3) works in concert with other co-regulator molecules to determine suppressive phenotype of Treg. Compiling evidence show that aberrant TFH, GC responses and deficiencies of Treg are associated with systemic lupus erythematous and autoantibody production. We induce pristane nephropathy on T cell specific miR-17–92 knockout (miR-17–92−/−) mice. Mir17-92 T cell specific deficiency mitigates pristane induced-lupus nephropathy in mice. The mice showed less TFH cells, less GC B cells and lower autoantibody formation. Consistent with the reduction in autoantibody production, histological analysis revealed a lower mean renal histopathology score and less compliment deposition. We demonstrate that the miR17-92 cluster regulates TFH development by targeting Akt pathway. Moreover, miR17-92 mitigate the suppression function of Tregs by targeting Foxp3 co-regulators. Ectopic expression of miR17-92 downmodulates the suppression functions of Tregs and provides Tregs with partial effector activity via de-repression of cytokine genes. Our studies suggest that miR17-92 modulates lupus activity through critical regulation in TFH and Treg, unveiling the future therapeutic potential of microRNA manipulation in lupus nephritis.