Mir-17–92 regulates bone marrow homing of plasma cells and production of immunoglobulin G2c

• Published in: Nature communications Vol. 6; no. 1; p. 6764
• Main Authors: Xu, Shengli, Ou, Xijun, Huo, Jianxin, Lim, Kristen, Huang, Yuhan, Chee, Sheena, Lam, Kong-Peng
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 17.04.2015; Nature Publishing Group
• Subjects: 13/1; 13/106; 13/109; 13/31; 13/44; 13/51; 14/19; 38; 38/15; 631/250/1619/40/1742; 631/250/2152/2153/1291; 631/250/232/2058; 631/337/384/331; Animals; Antibodies, Antinuclear - biosynthesis; B-Lymphocytes - immunology; Bone Marrow - immunology; Cell Differentiation - genetics; Cell Differentiation - immunology; Cell Movement - genetics; Cell Movement - immunology; Flow Cytometry; Glomerulonephritis - genetics; Glomerulonephritis - immunology; Humanities and Social Sciences; Ikaros Transcription Factor - genetics; Ikaros Transcription Factor - metabolism; Immune Complex Diseases - genetics; Immune Complex Diseases - immunology; Immunoglobulin G - biosynthesis; Mice; MicroRNAs - genetics; MicroRNAs - immunology; multidisciplinary; Plasma Cells - immunology; Protein Tyrosine Phosphatase, Non-Receptor Type 6 - genetics; Receptors, Lysosphingolipid - genetics; Receptors, Lysosphingolipid - metabolism; Science; Science (multidisciplinary); T-Lymphocytes - immunology
• DOI: 10.1038/ncomms7764
• ISSN: 2041-1723

The polycistronic mir-17–92 cluster, also known as oncomir-1 , was previously shown to be essential for early B lymphopoiesis. However, its role in late-stage B-cell differentiation and function remains unexplored. Here we ablate mir-17–92 in mature B cells and demonstrate that mir-17–92 is dispensable for conventional B-cell development in the periphery. Interestingly, mir-17–92 -deficiency in B cells leads to enhanced homing of plasma cells to the bone marrow during T-cell-dependent immune response and selectively impairs IgG2c production. Mechanistically, mir-17–92 directly represses the expression of Sphingosine 1-phosphate receptor 1 and transcription factor IKAROS, which are, respectively, important for plasma cell homing and IgG2c production. We further show that deletion of mir-17–92 could reduce IgG2c anti-DNA autoantibody production and hence mitigate immune complex glomerulonephritis in Shp1-deficient mice prone to autoimmunity. Our results identify important roles for mir-17–92 in the regulation of peripheral B-cell function. After activation and selection, plasma cells home to the bone marrow where they persist and continue to make antibodies. Here the authors show that the mir-17–92 cluster coordinates the process by regulating the homing receptor S1PR1 and the transcription factor IKAROS that controls IgG2c production.