Distinct transcriptomic features are associated with transitional and mature B-cell populations in the mouse spleen

Eden Kleiman, Daria Salyakina, Magali De Heusch, Kristen L. Hoek, Joan M. Llanes, Iris Castro, Jacqueline A. Wright, Emily S. Clark, Derek M Dykxhoorn, Enrico Capobianco, Akiko Takeda, Jean Christophe Renauld, Wasif Khan

Research output: Contribution to journalArticle

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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.

Original languageEnglish (US)
Article number00030
JournalFrontiers in Immunology
Volume6
Issue numberFEB
DOIs
StatePublished - 2015

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B-Lymphoid Precursor Cells
B-Lymphocytes
Spleen
Population
B-Lymphocyte Subsets
Cell Differentiation
Interleukin-9
Peripheral Tolerance
Phosphoprotein Phosphatases
Autoimmunity
Phosphatidylinositol 3-Kinases
Transcriptome
Transgenic Mice
Genes
Up-Regulation
Down-Regulation
RNA

Keywords

  • DAP10 PI3K pathway
  • Follicular 1 and 2 B-cells
  • IL-9/IL-9R
  • Marginal zone B-cells
  • Myb Myc
  • Splenic transitional B-cells
  • Toll-like receptors 3 and 7
  • Transcriptome by RNA-seq technique

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy

Cite this

Distinct transcriptomic features are associated with transitional and mature B-cell populations in the mouse spleen. / Kleiman, Eden; Salyakina, Daria; De Heusch, Magali; Hoek, Kristen L.; Llanes, Joan M.; Castro, Iris; Wright, Jacqueline A.; Clark, Emily S.; Dykxhoorn, Derek M; Capobianco, Enrico; Takeda, Akiko; Renauld, Jean Christophe; Khan, Wasif.

In: Frontiers in Immunology, Vol. 6, No. FEB, 00030, 2015.

Research output: Contribution to journalArticle

Kleiman, E, Salyakina, D, De Heusch, M, Hoek, KL, Llanes, JM, Castro, I, Wright, JA, Clark, ES, Dykxhoorn, DM, Capobianco, E, Takeda, A, Renauld, JC & Khan, W 2015, 'Distinct transcriptomic features are associated with transitional and mature B-cell populations in the mouse spleen', Frontiers in Immunology, vol. 6, no. FEB, 00030. https://doi.org/10.3389/fimmu.2015.00030
Kleiman, Eden ; Salyakina, Daria ; De Heusch, Magali ; Hoek, Kristen L. ; Llanes, Joan M. ; Castro, Iris ; Wright, Jacqueline A. ; Clark, Emily S. ; Dykxhoorn, Derek M ; Capobianco, Enrico ; Takeda, Akiko ; Renauld, Jean Christophe ; Khan, Wasif. / Distinct transcriptomic features are associated with transitional and mature B-cell populations in the mouse spleen. In: Frontiers in Immunology. 2015 ; Vol. 6, No. FEB.
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AU - Llanes, Joan M.

AU - Castro, Iris

AU - Wright, Jacqueline A.

AU - Clark, Emily S.

AU - Dykxhoorn, Derek M

AU - Capobianco, Enrico

AU - Takeda, Akiko

AU - Renauld, Jean Christophe

AU - Khan, Wasif

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