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.
This is a preview of subscription content, access via your institution
Access options
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
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.
References
Tokoyoda, K., Egawa, T., Sugiyama, T., Choi, B.I. & Nagasawa, T. Cellular niches controlling B lymphocyte behavior within bone marrow during development. Immunity 20, 707–718 (2004).
Hardy, R.R. B-cell commitment: deciding on the players. Curr. Opin. Immunol. 15, 158–165 (2003).
Allman, D., Srivastava, B. & Lindsley, R.C. Alternative routes to maturity: branch points and pathways for generating follicular and marginal zone B cells. Immunol. Rev. 197, 147–160 (2004).
Lyman, S.D. & Jacobsen, S.E.W. c-kit ligand and Flt3 ligand: stem/progenitor cell factors with overlapping yet distinct activities. Blood 91, 1101–1134 (1998).
Schiemann, B. et al. An essential role for BAFF in the normal development of B cells through a BCMA-independent pathway. Science 293, 2111–2114 (2001).
Reche, P.A. et al. Human thymic stromal lymphopoietin preferentially stimulates myeloid cells. J. Immunol. 167, 336–343 (2001).
Pandey, A. et al. Cloning of a receptor subunit required for signaling by thymic stromal lymphopoietin. Nat. Immunol. 1, 59–64 (2000).
Park, L.S. et al. Cloning of the murine thymic stromal lymphopoietin (TSLP) receptor: Formation of a functional heteromeric complex requires interleukin 7 receptor. J. Exp. Med. 192, 659–670 (2000).
Friend, S.L. et al. A thymic stromal cell line supports in vitro development of surface IgM+ B cells and produces a novel growth factor affecting B and T lineage cells. Exp. Hematol. 22, 321–328 (1994).
Levin, S.D. et al. Thymic stromal lymphopoietin: a cytokine that promotes the development of IgM+ B cells in vitro and signals via a novel mechanism. J. Immunol. 162, 677–683 (1999).
Ray, R.J., Furlonger, C., Williams, D.E. & Paige, C.J. Characterization of thymic stromal-derived lymphopoietin (TSLP) in murine B cell development in vitro. Eur. J. Immunol. 26, 10–16 (1996).
Soumelis, V. et al. Human epithelial cells trigger dendritic cell mediated allergic inflammation by producing TSLP. Nat. Immunol. 3, 673–680 (2002).
Ying, S. et al. Thymic stromal lymphopoietin expression is increased in asthmatic airways and correlates with expression of Th2-attracting chemokines and disease severity. J. Immunol. 174, 8183–8190 (2005).
Zhou, B. et al. Thymic stromal lymphopoietin as a key initiator of allergic airway inflammation in mice. Nat. Immunol. 6, 1047–1053 (2005).
Yoo, J. et al. Spontaneous atopic dermatitis in mice expressing an inducible thymic stromal lymphopoietin transgene specifically in the skin. J. Exp. Med. 202, 541–549 (2005).
Liu, Y.J. Thymic stromal lymphopoietin: master switch for allergic inflammation. J. Exp. Med. 203, 269–273 (2006).
Taneda, S. et al. Cryoglobulinemic glomerulonephritis in thymic stromal lymphopoietin transgenic mice. Am. J. Pathol. 159, 2355–2369 (2001).
Osborn, M.J. et al. Overexpression of murine TSLP impairs lymphopoiesis and myelopoiesis. Blood 103, 843–851 (2004).
Diamond, I., Owolabi, T., Marco, M., Lam, C. & Glick, A. Conditional gene expression in the epidermis of transgenic mice using the tetracycline-regulated transactivators tTA and rTA linked to the keratin 5 promoter. J. Invest. Dermatol. 115, 788–794 (2000).
Li, Y.-S., Wasserman, R., Hayakawa, K. & Hardy, R.R. Identification of the earliest B lineage stage in mouse bone marrow. Immunity 5, 527–535 (1996).
Hardy, R.R., Carmack, C.E., Shinton, S.A., Kemp, J.D. & Hayakawa, K. Resolution and characterization of pro-B and pre-pro-B cell stages in normal mouse bone marrow. J. Exp. Med. 173, 1213–1225 (1991).
Vosshenrich, C.A., Cumano, A., Muller, W., Di Santo, J.P. & Vieira, P. Thymic stromal-derived lymphopoietin distinguishes fetal from adult B cell development. Nat. Immunol. 4, 773–779 (2003).
Vosshenrich, C.A., Cumano, A., Muller, W., Di Santo, J.P. & Vieira, P. Pre-B cell receptor expression is necessary for thymic stromal lymphopoietin responsiveness in the bone marrow but not in the liver environment. Proc. Natl. Acad. Sci. USA 101, 11070–11075 (2004).
Isaksen, D.E. et al. Uncoupling of proliferation and Stat5 activation in thymic stromal lymphopoietin-mediated signal transduction. J. Immunol. 168, 3288–3294 (2002).
Su, T.T., Guo, B., Wei, B., Braun, J. & Rawlings, D.J. Signaling in transitional type 2 B cells is critical for peripheral B-cell development. Immunol. Rev. 197, 161–178 (2004).
Martin, F. & Kearney, J.F. Marginal-zone B cells. Nat. Rev. Immunol. 2, 323–335 (2002).
Srivastava, B., Quinn, W.J., III, Hazard, K., Erikson, J. & Allman, D. Characterization of marginal zone B cell precursors. J. Exp. Med. 202, 1225–1234 (2005).
Saito, T. et al. Notch2 is preferentially expressed in mature B cells and indispensable for marginal zone B lineage development. Immunity 18, 675–685 (2003).
Berland, R. & Wortis, H.H. Origins and functions of B-1 cells with notes on the role of CD5. Annu. Rev. Immunol. 20, 253–300 (2002).
Montecino-Rodriguez, E., Leathers, H. & Dorshkind, K. Identification of a B-1 B cell–specified progenitor. Nat. Immunol. 7, 293–301 (2006).
Reynolds, P.J. et al. Changes in the relative abundance of type I and type II lck mRNA transcripts suggest differential promoter usage during T-cell development. Mol. Cell. Biol. 10, 4266–4270 (1990).
Carpino, N. et al. Absence of an essential role for thymic stromal lymphopoietin receptor in murine B-cell development. Mol. Cell. Biol. 24, 2584–2592 (2004).
Ferri, C., La Civita, L., Longombardo, G., Zignego, A.L. & Pasero, G. Mixed cryoglobulinaemia: a cross-road between autoimmune and lymphoproliferative disorders. Lupus 7, 275–279 (1998).
Sims, J.E. et al. Molecular cloning and biological characterization of a novel murine lymphoid growth factor. J. Exp. Med. 192, 671–680 (2000).
Fisher, A.G. et al. Lymphoproliferative disorders in an IL-7 transgenic mouse line. Leukemia 7, S66–S68 (1993).
Rich, B., Campos-Torres, J., Tepper, R., Moreadith, R. & Leder, P. Cutaneous lymphoproliferation and lymphomas in interleukin 7 transgenic mice. J. Exp. Med. 177, 305–316 (1993).
Mertsching, E., Grawunder, U., Meyer, V., Rolink, T. & Ceredig, R. Phenotypic and functional analysis of B lymphopoiesis in interleukin-7-transgenic mice: expansion of pro/pre-B cell number and persistence of B lymphocyte development in lymph nodes and spleen. Eur. J. Immunol. 26, 28–33 (1996).
Ceredig, R., Bosco, N., Maye, P.N., Andersson, J. & Rolink, A. In interleukin-7-transgenic mice, increasing B lymphopoiesis increases follicular but not marginal zone B cell numbers. Eur. J. Immunol. 33, 2567–2576 (2003).
Brunner, C. et al. B cell-specific transgenic expression of Bcl2 rescues early B lymphopoiesis but not B cell responses in BOB.1/OBF.1-deficient mice. J. Exp. Med. 197, 1205–1211 (2003).
Craxton, A., Draves, K.E., Gruppi, A. & Clark, E.A. BAFF regulates B cell survival by downregulating the BH3-only family member Bim via the ERK pathway. J. Exp. Med. 202, 1363–1374 (2005).
Kantor, A., Stall, A., Adams, S. & Herzenberg, L. Differential development of progenitor activity for three B-cell lineages. Proc. Natl. Acad. Sci. USA 89, 3320–3324 (1992).
Herzenberg, L.A., Tung, J., Moore, W.A. & Parks, D.R. Interpreting flow cytometry data: a guide for the perplexed. Nat. Immunol. 7, 681–685 (2006).
Gazit, R., Krizhanovsky, V. & Ben-Arie, N. Math1 controls cerebellar granule cell differentiation by regulating multiple components of the Notch signaling pathway. Development 131, 903–913 (2004).
Pfaffl, M.W. A new mathematical model for relative quantification in real-time RT-PCR. Nucleic Acids Res. 29, e45 (2001).
Cariappa, A. et al. The CD9 tetraspanin is not required for the development of peripheral B cells or for humoral immunity. J. Immunol. 175, 2925–2930 (2005).
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
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
Ethics declarations
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)
Rights and permissions
About this article
Cite this article
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
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/ni1452