Stages of germinal center transit are defined by B cell transcription factor coexpression and relative abundance

G Cattoretti, R Shaknovich, PM Smith… - The Journal of …, 2006 - journals.aai.org
G Cattoretti, R Shaknovich, PM Smith, HM Jäck, VV Murty, B Alobeid
The Journal of Immunology, 2006journals.aai.org
The transit of T cell-activated B cells through the germinal center (GC) is controlled by
sequential activation and repression of key transcription factors, executing the pre-and post-
GC B cell program. B cell lymphoma (BCL) 6 and IFN regulatory factor (IRF) 8 are necessary
for GC formation and for its molecular activity in Pax5+ PU. 1+ B cells. IRF4, which is highly
expressed in BCL6− GC B cells, is necessary for class switch recombination and the plasma
cell differentiation at exit from the GC. In this study, we show at the single-cell level broad …
Abstract
The transit of T cell-activated B cells through the germinal center (GC) is controlled by sequential activation and repression of key transcription factors, executing the pre-and post-GC B cell program. B cell lymphoma (BCL) 6 and IFN regulatory factor (IRF) 8 are necessary for GC formation and for its molecular activity in Pax5+ PU. 1+ B cells. IRF4, which is highly expressed in BCL6− GC B cells, is necessary for class switch recombination and the plasma cell differentiation at exit from the GC. In this study, we show at the single-cell level broad coexpression of IRF4 with BCL6, Pax5, IRF8, and PU. 1 in pre-and post-GC B cells in human and mouse. IRF4 is down-regulated in BCL6+ human GC founder cells (IgD+ CD38+), is absent in GC centroblasts, and is re-expressed in positive regulatory domain 1-positive centrocytes, which are negative for all the B cell transcription factors. Activated (CD30+) and activation-induced cytidine deaminase-positive extrafollicular blasts coexpress Pax5 and IRF4. PU. 1-negative plasma cells and CD30+ blasts uniquely display the conformational epitope of IRF4 recognized by the MUM1 Ab, an epitope that is absent from any other IRF4+ PU. 1+ lymphoid and hemopoietic subsets. Low grade B cell lymphomas, representing the malignant counterpart of pre-and post-GC B cells, accordingly express IRF4. However, a fraction of BCL6+ diffuse large B cell lymphomas express IRF4 bearing the MUM1 epitope, indicative of a posttranscriptional modification of IRF4 not seen in the normal counterpart.
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