miR-29 Sustains B Cell Survival and Controls Terminal Differentiation via Regulation of PI3K Signaling
Marcus J. Hines,
Maryaline Coffre,
Tenny Mudianto,
Marisella Panduro,
Eric J. Wigton,
Cosmin Tegla,
Victoria Osorio-Vasquez,
Robin Kageyama,
David Benhamou,
Oriana Perez,
Sofia Bajwa,
Michael T. McManus,
K. Mark Ansel,
Doron Melamed,
Sergei B. Koralov
Affiliations
Marcus J. Hines
Department of Pathology, NYU School of Medicine, New York, NY 10016, USA
Maryaline Coffre
Department of Pathology, NYU School of Medicine, New York, NY 10016, USA
Tenny Mudianto
Department of Pathology, NYU School of Medicine, New York, NY 10016, USA
Marisella Panduro
Department of Microbiology and Immunology, UCSF, San Francisco, CA 94143, USA; Sandler Asthma Basic Research Center, UCSF, San Francisco, CA 94143, USA
Eric J. Wigton
Department of Microbiology and Immunology, UCSF, San Francisco, CA 94143, USA; Sandler Asthma Basic Research Center, UCSF, San Francisco, CA 94143, USA
Cosmin Tegla
Department of Pathology, NYU School of Medicine, New York, NY 10016, USA
Victoria Osorio-Vasquez
Department of Pathology, NYU School of Medicine, New York, NY 10016, USA
Robin Kageyama
Department of Microbiology and Immunology, UCSF, San Francisco, CA 94143, USA; Sandler Asthma Basic Research Center, UCSF, San Francisco, CA 94143, USA
David Benhamou
Department of Immunology, Faculty of Medicine, Technion, Haifa 31096, Israel
Oriana Perez
Department of Pathology, NYU School of Medicine, New York, NY 10016, USA
Sofia Bajwa
Department of Pathology, NYU School of Medicine, New York, NY 10016, USA
Michael T. McManus
Department of Microbiology and Immunology, UCSF, San Francisco, CA 94143, USA; Diabetes Center, UCSF, San Francisco, CA 94143, USA
K. Mark Ansel
Department of Microbiology and Immunology, UCSF, San Francisco, CA 94143, USA; Sandler Asthma Basic Research Center, UCSF, San Francisco, CA 94143, USA
Doron Melamed
Department of Immunology, Faculty of Medicine, Technion, Haifa 31096, Israel; Corresponding author
Sergei B. Koralov
Department of Pathology, NYU School of Medicine, New York, NY 10016, USA; Corresponding author
Summary: The phosphatidylinositol 3-kinase (PI3K) signaling cascade downstream of the B cell receptor (BCR) signalosome is essential for B cell maturation. Proper signaling strength is maintained through the PI3K negative regulator phosphatase and tensin homolog (PTEN). Although a role for microRNA (miRNA)-dependent control of the PTEN-PI3K axis has been described, the contribution of individual miRNAs to the regulation of this crucial signaling modality in mature B lymphocytes remains to be elucidated. Our analyses reveal that ablation of miR-29 specifically in B lymphocytes results in an increase in PTEN expression and dampening of the PI3K pathway in mature B cells. This dysregulation has a profound impact on the survival of B lymphocytes and results in increased class switch recombination and decreased plasma cell differentiation. Furthermore, we demonstrate that ablation of one copy of Pten is sufficient to ameliorate the phenotypes associated with miR-29 loss. Our data suggest a critical role for the miR-29-PTEN-PI3K regulatory axis in mature B lymphocytes.
