Abstract
Splenic transitional B-cells (T1 and T2) are selected to avoid self-reactivity and to safeguard against autoimmunity, then differentiate into mature follicular (FO-I and FO-II) and marginal zone (MZ) subsets. Transcriptomic analysis by RNA-seq of the five B-cell subsets revealed T1 cell signature genes included RAG suggesting a potential for receptor revision. T1 to T2 B-cell differentiation was marked by a switch from Myb to Myc, increased expression of the PI3K adapter DAP10 and MHC class II. FO-II may be an intermediate in FO-I differentiation and may also become MZ B-cells as suggested by principle component analysis. MZ B-cells possessed the most distinct transcriptome including down-regulation of CD45 phosphatase-associated protein (CD45-AP/PTPRC-AP), as well as upregulation of IL-9R and innate molecules TLR3, TLR7, and bactericidal Perforin-2 (MPEG1). Among the endosomal TLRs, stimulation via TLR3 further enhanced Perforin-2 expression exclusively in MZ B-cells. Using gene-deleted and overexpressing transgenic mice we show that IL-9/IL-9R interaction resulted in rapid activation of STAT1, 3, and 5, primarily in MZ B-cells. Importantly, CD45-AP mutant mice had reduced transitional and increased mature MZ and FO B-cells, suggesting that it prevents premature entry of transitional B-cells to the mature B-cell pool or their survival and proliferation. Together, these findings suggest, developmental plasticity among splenic B-cell subsets, potential for receptor revision in peripheral tolerance whereas enhanced metabolism coincides with T2 to mature B-cell differentiation. Further, unique core transcriptional signatures in MZ B-cells may control their innate features.
Highlights
The role of B-lymphocytes is to produce antigen specific antibodies to neutralize pathogens
B-cells develop in the bone marrow (BM) where most autoreactive clones are triaged by the central tolerance mechanisms of clonal deletion, anergy, or receptor editing [1]
Additional experiments showed that in addition to Stat3, IL-9 induced phosphorylation of Stat1 and Stat5 in marginal zone (MZ) B-cells. These experiments were carried out with B-cells isolated from Balb/c mice, the results demonstrate that selective responsiveness of MZ B-cells to IL-9 is independent of the genetic background (Figures 8M–O)
Summary
The role of B-lymphocytes is to produce antigen specific antibodies to neutralize pathogens. B-cells develop in the bone marrow (BM) where most autoreactive clones are triaged by the central tolerance mechanisms of clonal deletion, anergy, or receptor editing [1]. Surviving sIgM+ immature or transitional 1 (T1) B-cells migrate to the spleen, where they are again tested for autoreactivity. Innocuous clones are allowed to develop into transitional 2 (T2) cells [2]. Observations that T1 cells are extremely sensitive to BCR-induced apoptosis in vitro suggest that the T1-stage serves as a peripheral tolerance checkpoint [3,4,5,6,7]. Dysregulation of peripheral checkpoint can lead to autoimmune pathologies such as SLE, RA, and MS [8,9,10]
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