Micromanaging Autoimmune Nephritis: miR-17-92 Modulates T<sub>FH</sub> Development and Regulatory T Cell Activity
November 09, 2019 | 10:00 AM - 12:00 PM
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Micromanaging Autoimmune Nephritis: miR-17-92 Modulates TFH Development and Regulatory T Cell Activity
Glomerular Diseases: Immunology, Inflammation - II
November 09, 2019 | Location: Exhibit Hall, Walter E. Washington Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Glomerular Diseases
- 1202 Glomerular Diseases: Immunology and Inflammation
- Yang, Huang-Yu, Chang Gung Memorial Hospital, Taoyuan, Taiwan
T follicular helper (TFH) cell provide crucial growth signals to germinal center (GC) B cells supporting antibody production.Tight control of TFHnumbers 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 erythematousand autoantibody production.
We generated T cell specific miR-17-92 knockout (miR-17-92-/-) mice, followed by induction of pristane nephropathy in miR-17-92 -/- and wild type littermates. By bioinformatics study, possible targets of mir-17-92, related to Treg function was evaluated. Luciferase reporter assay was utilized for verification. Forced expression and knockdown of miRNA in Treg and TFH was performed by lentivirus.
We induce pristane nephropathy on T cell specific miR-17-92 knockout (miR-17-92-/-) mice. Mir17-92 CD4 T cell specific deficiencymitigates pristane induced-lupus nephropathy in mice. The mice showed less TFHcells, 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 IgG deposition. We further demonstrate that the miR-17 regulates TFHdevelopment by targeting Akt pathway. Moreover, miR17-92 mitigate the suppression function of Tregs by targeting Foxp3 co-regulators. Ectopic expression of miR-17 downmodulates the suppression functions of Tregs in the colitis model. In addition, Tregs from patient with lupus nephritis and lupus mice both showed increased miR-17 expression.
Our studies suggest that miR-17-92 modulates aberrant immune response through critical regulation in T cells subsets, unveiling the future therapeutic potential of microRNA manipulation in lupus nephritis.
- Private Foundation Support