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Local increase in thymic stromal lymphopoietin induces systemic alterations in B cell development

An Erratum to this article was published on 01 July 2007

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Abstract

The cytokine thymic stromal lymphopoietin (TSLP) drives immature B cell development in vitro and may regulate T helper type 2 responses. Here we analyzed the involvement of TSLP in B cell development in vivo with a doxycycline-inducible, keratin 5–driven transgene encoding TSLP (K5-TSLP). K5-TSLP-transgenic mice given doxycycline showed an influx of immature B cells into the periphery, with population expansion of follicular mature B cells, near-complete loss of marginal zone and marginal zone precursor B cells, and 'preferential' population expansion of peritoneal B-1b B cells. These changes promoted cryoglobulin production and immune complex–mediated renal disease. Identical events occurred in mice without T cells, in alternative TSLP-transgenic models and in K5-TSLP-transgenic mice with undetectable systemic TSLP. These observations suggest that signals mediating localized TSLP expression may modulate systemic B cell development and promote humoral autoimmunity.

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Figure 1: Doxycyline treatment correlates with influx of immature B cells into the periphery.
Figure 2: TSLP directly stimulates the population expansion of early B cell precursors in the bone marrow.
Figure 3: Population expansion of both splenic transitional and follicular mature B cells in K5-TSLP mice.
Figure 4: K5-TSLP mice lack marginal zone and marginal zone precursor B cells.
Figure 5: TSLP overexpression promotes the population expansion of peritoneal B-1b B cells and B-1 progenitors in the bone marrow.
Figure 6: The B cell phenotype of K5-TSLP mice requires TSLPR expression and occurs in other models of TSLP overexpression.
Figure 7: B cell population expansion in K5-TSLP mice leads to cryoglobulinemia and higher antibody production.

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Change history

  • 30 May 2007

    In the version of this article initially published, the second subheading on page 523 is incorrect. The correct subheading should be TSLP stimulates the population expansion of late pro–B cells. The error has been corrected in the HTML and PDF versions of the article.

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Acknowledgements

We thank J. Foley and M. Wener for help with cryoglobulin typing, and S. Khim for animal husbandry. Supported by the National Institutes of Health (R01 HD37091, R01 AI44259, R01 AI068731, R01 DK072295 and R01 DK66802 to C.E.A., and P30 DK47754).

Author information

Authors and Affiliations

Authors

Contributions

D.J.R. and S.F.Z. designed experiments; A.A, M.O., T.N. S.B.-H., M.I. and T.A. designed and did experiments; K.H. and C.E.A. contributed reagents and did kidney immunochemistry; J.D. and A.F generated transgenic mice and contributed reagents; and A.A., S.F.Z. and D.J.R. wrote the paper.

Corresponding authors

Correspondence to Steven F Ziegler or David J Rawlings.

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Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Fig. 1

K5-TSLP animals have normal relative proportion of total splenic B cells, yet lack CD1d+ MZP and MZ B cells. (PDF 32 kb)

Supplementary Fig. 2

B-1 cells lack IL-7Rα and expand in neonatal Lck-TSLP animals. (PDF 57 kb)

Supplementary Fig. 3

Expansion of early B cell subsets in K5-TSLP mice is T cell independent. (PDF 119 kb)

Supplementary Fig. 4

K5-TSLP mice exhibit cryoglobulin formation. (PDF 24 kb)

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Astrakhan, A., Omori, M., Nguyen, T. et al. Local increase in thymic stromal lymphopoietin induces systemic alterations in B cell development. Nat Immunol 8, 522–531 (2007). https://doi.org/10.1038/ni1452

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