To the editor:
In the August 2003 issue of Nature Immunology1, as well as in later studies2, Voβhenrich et al. presented experimental data on the cytokine requirements of developing B cells, which led them to conclude that “TSLP [thymic stromal lymphopoietin] is the factor responsible for most of the fetal and perinatal B cell production that takes place when the IL-7–γc [interleukin 7–common γ-chain] signaling pathway is disrupted.”1 Although the data reported were technically sound and compatible with such a conclusion, the authors did not provide direct evidence to support (or exclude) the idea of a critical function for TSLP in IL-7-independent fetal B lymphopoiesis. The conclusions of Voβhenrich et al. were based on the demonstration that B lymphopoiesis was much more affected (tenfold more) in mice deficient in IL-7 receptor α-chain, essential for IL-7 as well as TSLP signaling, than in mice deficient in the common γ-chain (γc), required for IL-7 but not TSLP-mediated signaling3,4. However, these data could at best be considered strong indirect support for the idea of TSLP as the main cytokine driving IL-7-independent fetal B lymphopoiesis, as there could be other reasons for a difference in the phenotypes of γc-deficient mice and those deficient in the IL-7 receptor α-chain. Furthermore, Voβhenrich et al. used bone marrow of mice 4–12 weeks of age, not fetal liver, for their comparative in vivo analysis of B lymphopoiesis in these mice1,2. Instead, the extrapolation to the idea that TSLP is key to the fetal stages of B lymphopoiesis was based on the finding that fetal but not adult pro–B cells were responsive to TSLP in vitro1,2. In contrast, a lack of an important function for TSLP in adult B lymphopoiesis has been indicated by studies of TSLP receptor–deficient (Tpte2−/−) mice5,6.
As fetal lymphopoiesis had not been examined in singly deficient Tslp−/− or Tpte2−/− mice, we investigated B lymphopoiesis in the livers of Tpte2−/− mice at embryonic day 17.5 but found no deficiency in Tpte2−/− fetuses at any stage of B cell development (Fig. 1a and Supplementary Fig. 1 online). Furthermore, when comparing B lymphopoiesis in the fetal livers of Il7−/− and Il7−/−Tpte2−/− mice, we obtained no evidence for substantial involvement of TSLP in IL-7-independent regulation of fetal pro–B cells or pre–B cells, whereas we noted a slight additional reduction in the number of immature B cells in Il7−/−Tpte2−/− fetuses relative to that in Il7−/− fetuses (Fig. 1b and Supplementary Fig. 1). Thus, although Voβhenrich et al. provided compelling evidence that fetal pro–B cells are highly responsive to TSLP1, our studies of Tpte2−/− and Il7−/−Tpte2−/− fetuses fail to support their claim that TSLP is the most important cytokine promoting IL-7-independent fetal B lymphopoiesis. Instead, although Voβhenrich et al. also concluded that “Flk-2 is involved, but TSLP is the main factor driving IL-7-independent fetal and perinatal lymphopoiesis,”1 we have done additional studies of mice deficient in the cytokine Flt3L (also called Flk-2 ligand) and IL-7 (Flt3l−/−Il7−/− mice) and of Flt3l−/−Tpte2−/− mice and have found that the reported complete loss of B-1 as well as B-2 B lymphopoiesis in Flt3l−/−Il7r−/− mice7 and Flk2−/−Il7r−/− mice1 is entirely due to the simultaneous loss of function of IL-7 and Flt3L (C.T.J. and S.E.W.J., unpublished observations). Collectively, our findings suggest that Flt3L rather than TSLP is the key regulator of IL-7-independent B lymphopoiesis and that intact TSLP function is insufficient to restore any detectable B lymphopoiesis in the absence of these two critical regulators of B cell progenitors.
Note: Supplementary information is available on the Nature Immunology website.
References
Voβhenrich, C.A., Cumano, A., Muller, W., Di Santo, J.P. & Vieira, P. Nat. Immunol. 4, 773–779 (2003).
Vosshenrich, C.A., Cumano, A., Muller, W., Di Santo, J.P. & Vieira, P. Proc. Natl. Acad. Sci. USA 101, 11070–11075 (2004).
Friend, S.L. et al. Exp. Hematol. 22, 321–328 (1994).
Levin, S.D. et al. J. Immunol. 162, 677–683 (1999).
Al-Shami, A. et al. J. Exp. Med. 200, 159–168 (2004).
Carpino, N. et al. Mol. Cell. Biol. 24, 2584–2592 (2004).
Sitnicka, E. et al. J. Exp. Med. 198, 1495–1506 (2003)
Author information
Authors and Affiliations
Ethics declarations
Competing interests
The authors declare no competing financial interests.
Supplementary information
Supplementary Text and Figures
Supplementary Figure 1 (PDF 509 kb)
Rights and permissions
About this article
Cite this article
Jensen, C., Kharazi, S., Böiers, C. et al. TSLP-mediated fetal B lymphopoiesis?. Nat Immunol 8, 897 (2007). https://doi.org/10.1038/ni0907-897
Issue Date:
DOI: https://doi.org/10.1038/ni0907-897