Abstract
Strict control of B lymphocyte development is required for the ability to mount humoral immune responses to diverse foreign antigens while remaining self-tolerant. In the bone marrow, B lineage cells transit through several developmental stages in which they assemble a functional B cell receptor in a stepwise manner. The immunoglobulin heavy chain gene is rearranged at the pro-B stage. At the large pre-B stage, cells with a functional heavy chain expand in response to signals from IL-7 and the pre-BCR. Cells then cease proliferation at the small pre-B stage and rearrange the immunoglobulin light chain gene. The fully formed BCR is subsequently expressed on the surface of immature B cells and autoreactive cells are culled by central tolerance mechanisms. Once in the periphery, transitional B cells develop into mature B cell subsets such as marginal zone and follicular B cells. These developmental processes are controlled by transcription factor networks, central to which are IRF4 and IRF8. These were thought to act redundantly during B cell development in the bone marrow, with their functions diverging in the periphery where IRF4 limits the number of marginal zone B cells and is required for germinal center responses and plasma cell differentiation. Because of IRF4’s unique role in mature B cells, we hypothesized that it may also have functions earlier in B cell development that cannot be compensated for by IRF8. Indeed, we find that IRF4 has a unique role in upregulating the pre-B cell marker CD25, limiting IL-7 responsiveness, and promoting migration to CXCR4 such that IRF4-deficient mice have a partial block at the pre-B cell stage. We also find that IRF4 acts in early transitional B cells to restrict marginal zone B cell development, as deletion of IRF4 in mature B cells with CD21-cre impairs plasma cell differentiation but has no effect on marginal zone B cell numbers. These studies highlight IRF4 as the dominant IRF family member in early B lymphopoiesis.
Highlights
During B cell development in the bone marrow, a tightly controlled series of events ensures that functional B cells are produced that can recognize an almost infinite number of foreign antigens while limiting the escape of autoreactive B cells into the periphery [reviewed in [1, 2]]
While B220+CD43+IgMpro-B cells were present in normal numbers, there was a significant reduction in the numbers of B220+CD43-IgM- pre B cells, B220+CD43-IgM+ immature B cells, and B220hiIgM+ mature B cells in IRF4-deficient mice (Figures 1A, D, E)
Based on the study of IRF4/IRF8 double knockout mice and the reconstitution of pre-B cells from these animals with either IRF4 or IRF8, it has been thought that IRF4 and IRF8 are redundant for early B cell developmental events
Summary
During B cell development in the bone marrow, a tightly controlled series of events ensures that functional B cells are produced that can recognize an almost infinite number of foreign antigens while limiting the escape of autoreactive B cells into the periphery [reviewed in [1, 2]]. The immunoglobulin (Ig) genes are rearranged sequentially and tested during this process, beginning with the Ig heavy chain at the pro-B cell stage. Successful pairing of the expressed heavy chain with the surrogate light chain promotes a proliferative expansion at the large pre-B cell stage. IL-7 promotes expansion of pro-B and large pre-B cells. At the small pre-B cell stage, cells exit the cell cycle and rearrange the Ig light chain genes. The transition between the large and small pre-B stage is driven by a particular mode of pre-BCR signaling dependent on the adaptor molecule BLNK ( known as SLP-65) [3, 4], loss of IL-7 signaling [3, 5], and CXCL12/CXCR4 responses [5, 6]. Cells transition to the immature B stage where they express the BCR on the surface and are tested for autoreactivity by central tolerance mechanisms
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