Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2007 Oct 29;204(11):2545-52.
doi: 10.1084/jem.20071401. Epub 2007 Oct 15.

Autocrine/paracrine TGFbeta1 is required for the development of epidermal Langerhans cells

Daniel H Kaplan  1 , Ming O Li, Matthew C Jenison, Warren D Shlomchik, Richard A Flavell, Mark J Shlomchik
Affiliations

Autocrine/paracrine TGFbeta1 is required for the development of epidermal Langerhans cells

Daniel H Kaplan et al. J Exp Med. .

Abstract

Langerhans cells (LCs) are bone marrow (BM)-derived epidermal dendritic cells (DCs) that develop from precursors found in the dermis. Epidermal LCs are absent in transforming growth factor (TGF) beta1-deficient mice. It is not clear whether TGFbeta1 acts directly on LC precursors to promote maturation or whether it acts on accessory cells, which in turn affect LC precursors. In addition, the physiologic source of TGFbeta1 is uncertain because BM chimera experiments showed that neither hematopoietic nor nonhematopoietic-derived TGFbeta1 is required for LC development. To address these issues, we created mice transgenic for a bacterial artificial chromosome (BAC) containing the gene for human Langerin into which Cre recombinase had been inserted by homologous recombination (Langerin-Cre). These mice express Cre selectively in LCs, and they were bred to floxed TGFbetaRII and TGFbeta1 mice, thereby generating mice with LCs that either cannot respond to or generate TGFbeta1, respectively. Langerin-Cre TGFbetaRII mice had substantially reduced numbers of epidermal LCs, demonstrating that TGFbeta1 acts directly on LCs in vivo. Interestingly, Langerin-Cre TGFbeta1 mice also had very few LCs both in the steady state and after BM transplantation. Thus, TGFbeta1 derived from LCs acts directly on LCs through an autocrine/paracrine loop, and it is required for LC development and/or survival.

PubMed Disclaimer

Figures

Figure 1.
Figure 1.
Langerin-Cre transgene is expressed by all epidermal LCs. (A) Langerin-Cre mice were bred onto the Rosa26.EGFP Cre reporter line. FACS analysis of epidermal and dermal single-cell suspensions gated on live MHC-II+ cells (Tg+, thick line; Tg−, thin line with shading). (B) Analysis of live gated cutaneous LN cells from Tg+ (left) and Tg− (right) mice showing a population of CD11cint GFP+ cells in transgenic mice. (C) GFP+-gated cells from Cre+ mice are stained for DEC-205 (left, open) and CD8 (right, open), compared with an isotype control (filled).
Figure 2.
Figure 2.
Langerin-Cre is selectively expressed in skin-derived LCs. (A) FACS analysis of CD11c-gated live cells obtained from the indicated tissues of littermate control (top) or Langerin-Cre Rosa26.EGFP (bottom) mice stained for DEC-205. (B) Analysis of CD11c-gated live cells from the indicated tissue of Langerin-Cre mice stained for CD8α and Langerin.
Figure 3.
Figure 3.
LC development requires the direct action of TGFβ, and escaped LCs repopulate the epidermis in clusters. (A) FACS of live gated epidermal cells from Langerin-Cre TGFβRIIf/f (right) and littermate controls (left) stained for TGFβRII (top) or isotype control (bottom). (B) Each symbol represents the ratio of the percentage of epidermal LCs in an individual Langerin-Cre TGFβRIIf/f mouse compared with a sex- and age-matched control. The percentage of LCs in Langerin-Cre TGFβRIIf/f increases with age. P < 0.05. (C) Immunofluorescence of epidermal whole mounts from Langerin-Cre TGFβRIIf/f at the indicated age or WT mice stained for MHC-II (green). The majority of fields lack LCs. Representative fields that contain LCs are shown. Bars: (Day 22) 37.5 μm; (Days 60 and 89 and WT) 75 μm.
Figure 4.
Figure 4.
Steady-state LC development requires LC-derived TGFβ1. (A) A representative FACS analysis of live gated epidermal cells from 4-wk-old Langerin-Cre TGFβ1f/f (right) compared with control mice (left). (B) Each symbol represents the percentage of LCs in an individual Langerin-Cre TGFβf/f mouse or control. (C) Immunofluorescence of epidermal whole mounts from Langerin-Cre TGFβ1f/f or WT mice stained for MHC-II (green) and Langerin (red). As with the Langerin-Cre TGFβRIIf/f, most fields lack LCs, and a representative field containing LCs is shown. Bar, 75 μm.
Figure 5.
Figure 5.
LC repopulation in chimeric mice requires LC-derived TGFβ1. BM chimeras were generated by transferring BM from either Langerin-Cre+ TGFβ1f/f mice (A and B, bottom rows) or littermate Langerin-Cre− TGFβ1f/f controls (A and B, top rows) into irradiated congenic B6.CD45.1 recipients. Recipients were either exposed to 450 mJ of UVC 1 d after transplant (A) or not irradiated (B). After 8 wk, immunofluorescence of epidermal ear whole mounts were stained for CD45.2 (green) and Langerin (red) to determine the presence of donor LCs. Representative data from three independent experiments are shown. Bar, 75 μm.
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Romani, N., S. Holzmann, C.H. Tripp, F. Koch, and P. Stoitzner. 2003. Langerhans cells - dendritic cells of the epidermis. APMIS. 111:725–740. - PubMed
    1. Hemmi, H., M. Yoshino, H. Yamazaki, M. Naito, T. Iyoda, Y. Omatsu, S. Shimoyama, J.J. Letterio, T. Nakabayashi, H. Tagaya, et al. 2001. Skin antigens in the steady state are trafficked to regional lymph nodes by transforming growth factor-beta1-dependent cells. Int. Immunol. 13:695–704. - PubMed
    1. Kripke, M.L., C.G. Munn, A. Jeevan, J.M. Tang, and C. Bucana. 1990. Evidence that cutaneous antigen-presenting cells migrate to regional lymph nodes during contact sensitization. J. Immunol. 145:2833–2838. - PubMed
    1. Larregina, A.T., A.E. Morelli, L.A. Spencer, A.J. Logar, S.C. Watkins, A.W. Thomson, and L.D. Falo Jr. 2001. Dermal-resident CD14+ cells differentiate into Langerhans cells. Nat. Immunol. 2:1151–1158. - PubMed
    1. Ginhoux, F., F. Tacke, V. Angeli, M. Bogunovic, M. Loubeau, X.M. Dai, E.R. Stanley, G.J. Randolph, and M. Merad. 2006. Langerhans cells arise from monocytes in vivo. Nat. Immunol. 7:265–273. - PMC - PubMed

Publication types