Transcriptional control of plasma cells by Ikaros and Aiolos

Antibody-secreting plasmablasts and plasma cells provide acute and long -term protection against infection through the generation of antibodies against a vast number of pathogens (foreign antigens). This enormous number of different antigen specificities in the polyclonal B cell population is accomplished by recombination of the immunoglobulin genes during early B cell development and is further diversified by affinity maturation, a process which introduces somatic mutations into the antigen-binding site upon antigen encounter. Competition for the uptake of antigen and subsequent presentation to T cells selects the best B cell clones to differentiate into an antibody-secreting effector cell. Activated B cells initially differentiate into short-lived, proliferating plasmablasts that subsequently migrated to survival niches in the bone marrow and develop into quiescent long-lived plasma cells, also referred to as memory plasma cells, which constitute the basis for successful vaccination strategy. Beside the changes in cell cycle and longevity, plasma cell differentiation involves further massive changes in gene expression. The most significant functional change is the switch from the membrane-bound immunoglobulin transcript totheplasmacell-specific secreted immunoglobulin transcript, encoding the antibody. The development to antibody -secreting cells is also accompanied by marked alterations of the cell morphology, which is caused by the upregulation of immunoglobulin gene transcription. The secretion of large amounts of immunoglobulin proteins requires an increase of the secretory machinery of the cell. These changes in cell identity, morphology and function are implemented by a massive reprogramming of the transcriptional network in plasma cells. To date, only a few transcription factors, including IRF4, Blimp1, XBP1, and the Ikaros transcription factor family, are known to control the terminal differentiation of B cells to plasma cells. IRF4 controls the initiation of differentiation and subsequent surviva l of plasma cells, Blimp1 determines the plasma cell fate and function, and XBP1 activates the transcriptional program which is essential for the massive increase of protein secretion. Finally, although two expressed members of the Ikaros transcription factor family, Ikaros and Aiolos, have been implicated in the control of plasma cells, their function is unknown. Using conditional gene deletion and acute protein degradation in antibody-producing plasma cells, we aim to define the transcriptional role of Ikaros and Aiolos in plasma cells.

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