Abstract
The E3 ubiquitin ligase Itch interacts with Foxo1 and targets it for ubiquitination and degradation during follicular helper T-cell differentiation, whereas the transcription factor Foxo1 plays a critical role in B-cell development. Thus, we proposed that Itch mediates B-cell differentiation. Unexpectedly, we found that Itch deficiency downregulated Foxo1 expression in B cells. Itch cKO (conditional knock out in B cells) mice had fewer pro-B cells in the bone marrow, more small resting IgM−IgD−B cells in the periphery, and lower B-cell numbers in the lymph nodes through decreased Foxo1-mediated IL-7Rα, RAG, and CD62L expression, respectively. Importantly, Itch deficiency reduced Foxo1 mRNA expression by up-regulating JunB-mediated miR-182. Finally, Foxo1 negatively regulated JunB expression by up-regulating Itch. Thus, we have identified a novel regulatory axis between Itch and Foxo1 in B cells, suggesting that Itch is essential for B-cell development.
Highlights
B cells and their antibodies are the central elements of humoral immunity and, as part of the adaptive immune system, protect against a nearly unlimited variety of pathogens
We found splenic IgM−IgD−, IgM+IgD−, and IgM+IgD+ B cells and B220+CD19+ CD43+IgM− pro B cells, B220+CD19+CD43−IgM− pre-B cells, and B220+CD19+CD43− IgM+IgD− immature B cells in bone marrow (BM) express Itch protein (Supplementary Figures 2a,b)
We found that compared with their WT littermates, Itch cKO mice had more total B cells in peripheral blood monocytes (PBMCs) and fewer B cells in bone marrow (BM) and lymph nodes (LNs) (Fig. 1a,b)
Summary
B cells and their antibodies are the central elements of humoral immunity and, as part of the adaptive immune system, protect against a nearly unlimited variety of pathogens. Recombination-activating gene (Rag) proteins appear to be expressed at this stage, promoting Ig gene recombination, which is required for the process of B lymphopoiesis[5] This rearrangement machinery is precisely regulated by several transcription factors, including PU.[1], E2A, early B-cell factor (EBF) and Pax[56,7]. Blocking antibodies against CD62L have been shown to inhibit lymphocyte binding to HEVs both in vitro and in vivo[13], whereas CD62L knockout mice display a 70% to 90% reduction in lymph node cellularity[14]. A recent study has shown that Itch is required for follicular helper T-cell (Tfh-cell) differentiation by associating with Foxo[1] and promoting its ubiquitination and degradation
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