An IRF4–MYC–mTORC1 Integrated Pathway Controls Cell Growth and the Proliferative Capacity of Activated B Cells during B Cell Differentiation In Vivo
Year: 2021
Type: article
Abstract: Cell division is an essential component of B cell differentiation to antibody-secreting plasma cells, with critical reprogramming occurring during the initial stages of B cell activation. However, a complete understanding of the factors that coordinate early reprogramming events in vivo remain to be determined. In this study, we examined the initial reprogramming by IRF4 in activated B cells using an adoptive transfer system and mice with a B cell-specific deletion of IRF4. IRF4-deficient B cells responding to influenza, NP-Ficoll and LPS divided, but stalled during the proliferative response. Gene expression profiling of IRF4-deficient B cells at discrete divisions revealed IRF4 was critical for inducing MYC target genes, oxidative phosphorylation, and glycolysis. Moreover, IRF4-deficient B cells maintained an inflammatory gene expression signature. Complementary chromatin accessibility analyses established a hierarchy of IRF4 activity and identified networks of dysregulated transcription factor families in IRF4-deficient B cells, including E-box binding bHLH family members. Indeed, B cells lacking IRF4 failed to fully induce Myc after stimulation and displayed aberrant cell cycle distribution. Furthermore, IRF4-deficient B cells showed reduced mTORC1 activity and failed to initiate the B cell-activation unfolded protein response and grow in cell size. Myc overexpression in IRF4-deficient was sufficient to overcome the cell growth defect. Together, these data reveal an IRF4-MYC-mTORC1 relationship critical for controlling cell growth and the proliferative response during B cell differentiation.
Source: The Journal of Immunology
Institution: Emory University
Language: English
Topic: T-cell and B-cell Immunology
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: green
Awards: G1030950460, Predoctoral Training Program in Genetics, Epigenetic Regulation of Plasma Cells Differentiation, G2503756298, Epigenetic Regulation of Memory B Cell Differentiation and Reactivation, G4038820660, G4490687961, Epigenetic instruction of memory B cell function and reactivation, G7299544053, Plasma Cells in Health and Disease
OpenAlex ID: W3197452737