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. 2003 Sep 1;198(5):823-30.
doi: 10.1084/jem.20020437.

The inducible CXCR3 ligands control plasmacytoid dendritic cell responsiveness to the constitutive chemokine stromal cell-derived factor 1 (SDF-1)/CXCL12

Béatrice Vanbervliet  1 , Nathalie Bendriss-Vermare, Catherine Massacrier, Bernhard Homey, Odette de Bouteiller, Francine Brière, Giorgio Trinchieri, Christophe Caux
Affiliations

The inducible CXCR3 ligands control plasmacytoid dendritic cell responsiveness to the constitutive chemokine stromal cell-derived factor 1 (SDF-1)/CXCL12

Béatrice Vanbervliet et al. J Exp Med. .

Abstract

The recruitment of selected dendritic cell (DC) subtypes conditions the class of the immune response. Here we show that the migration of human plasmacytoid DCs (pDCs), the blood natural interferon alpha-producing cells, is induced upon the collective action of inducible and constitutive chemokines. Despite expression of very high levels of CXCR3, pDCs do not respond efficiently to CXCR3 ligands. However, they migrate in response to the constitutive chemokine stromal cell-derived factor 1 (SDF-1)/CXCL12 and CXCR3 ligands synergize with SDF-1/CXCL12 to induce pDC migration. This synergy reflects a sensitizing effect of CXCR3 ligands, which, independently of a gradient and chemoattraction, decrease by 20-50-fold the threshold of sensitivity to SDF-1/CXCL12. Thus, the ability of the constitutive chemokine SDF-1/CXCL12 to induce pDC recruitment might be controlled by CXCR3 ligands released during inflammation such as in virus infection. SDF-1/CXCL12 and the CXCR3 ligands Mig/CXCL9 and ITAC/CXCL1 display adjacent expression both in secondary lymphoid organs and in inflamed epithelium from virus-induced pathologic lesions. Because pDCs express both the lymph node homing molecule l-selectin and the cutaneous homing molecule cutaneous lymphocyte antigen, the cooperation between inducible CXCR3 ligands and constitutive SDF-1/CXCL12 may regulate recruitment of pDCs either in lymph nodes or at peripheral sites of inflammation.

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Figures

Figure 1.
Figure 1.
pDCs do not respond to most inflammatory chemokines. (A) Quantitative PCR for chemokine receptors on FACS®-sorted pDCs. Results expressed as pg/50 ng total RNA were normalized using 18S RNA (mean of n = 3). (B) Enriched circulating blood DC subsets were rested for 2 h at 37°C and then studied in transwell (5-μm pore size) migration assay. Examples of CD11c FACS® profiles of gated HLA-DR+ lineage marker− migrating cells (representative of ≥ 10). (C) Responses of blood CD11c− pDCs and CD11c+ myeloid DCs to various chemokines. Each chemokine was tested over a wide range of concentrations (1–1,000 ng/ml) and only the optimal response is shown (n ≥ 5).
Figure 2.
Figure 2.
Potent activity of the constitutive chemokine SDF-1/CXCL12 and high CXCR4, CXCR3, and l-selectin expression on pDCs. CXCR4 (A), CXCR3 (B), and l-selectin (C) cell surface expression on DC population (representative of ≥3). For pDC CXCR4, expression was also analyzed after 2 h of preincubation at 37°C (A, dashed line). mRNA expression of CXCR4 and CXCR3 was also determined by quantitative PCR (D) on the same populations (results expressed as pg/50 ng total RNA were normalized using 18S RNA, mean of n = 3). Finally, optimal response to CXCR4 and CXCR3 ligands is shown for each DC population (E, mean of n ≥ 5).
Figure 3.
Figure 3.
CXCR3 ligands selectively induce pDCs to respond to low SDF-1/CXCL12 concentration. (A) Dose response to IP-10/CXCL10 of pDCs in the presence or absence of a low dose of SDF-1/CXCL12 (10 ng/ml). (B) Dose response to SDF-1/CXCL12 of pDCs in the presence or absence of 1 μg/ml IP-10/CXCL10. (C) Response of pDCs to all CXCR3 ligands (1 μg/ml), tested individually, in the presence or absence of a low dose of SDF-1/CXCL12 (10 ng/ml). (D) Dose response to SDF-1/CXCL12 of FACS®-sorted CD11c− pDCs and CD11c+ myeloid DCs in the presence or absence of 1 μg/ml IP-10/CXCL10. (E) Effects of 1 μg/ml IP-10/CXCL10 on the dose response to SDF-1/CXCL12 of various DC and T cell populations. Results are expressed as folds of IP-10–induced migration over that of SDF-1/CXCL12 alone (ratio migration index in SDF-1/CXCL12 + IP-10/CXCL10/migration index in SDF-1/CXCL12 alone). Results from n ≥ 3.
Figure 4.
Figure 4.
CXCR3 ligands prime pDCs to respond to low SDF-1/CXCL12 concentrations. (A) Experiments were performed as a typical transwell migration assay with 20 ng/ml SDF-1/CXCL12 and 1 μg/ml IP-10/CXCL10, except that the upper well can also contain a chemokine. When both the upper and lower wells contain the same chemokine, the migration was identical or lower to that in medium alone (not depicted). (B) Preincubation experiments wherein the cells were first incubated in the presence of 20 ng/ml SDF-1/CXCL12 and 1 μg/ml IP-10/CXCL10 for 1 h before performing the migration assay to both receptor ligands in transwell. When the same chemokine was used in the preincubation and in the migration assay, the migration was identical or lower to that in medium alone (not depicted). Results are from n ≥ 3. (C) pDCs were incubated in presence of 20 ng/ml SDF-1/CXCL12, 1 μg/ml IP-10/CXCL10, or medium for 1.5 h at 37°C before performing the staining for CXCR4 (representative of n = 3). (D) CLA expression was performed on the different DC populations and monocytes by triple or double staining (representative of n = 4).
Figure 5.
Figure 5.
Mig/CXCL9 and ITAC/CXCL11 expression in blood vessels of T cell area of tonsils and of inflamed epithelium, is adjacent to that of SDF-1/CXCL12 by epithelial cells and in close contact with IL-3R–expressing pDCs. (A) Immunohistochemistry in 6-μm tonsil serial sections fixed in acetone showing detection of Mig/CXCL9 by endothelial cells in the T cell area (b and c) and in the crypt (g) contacting epithelial cells expressing SDF-1/CXCL12 (e and f) and IL-3R+ pDCs (h and i) within the network of SDF-1/CXCL12+ epithelial cells. Isotype match controls were performed (a, the T cell area; d, the epithelial crypt). a–c, ×200; d–f, ×100; g–i, ×400. (B) Immunohistochemistry in 6-μm serial sections fixed in acetone from normal skin, psoriatic lesion, and biopsies of verrucae vulgaris and molluscum contagiosum showing Mig/CXCL9 (e–h) expression in lesions by cells contacting CD105+ blood vessels (i–l) and epithelial sites of constitutive SDF-1/CXCL12 expression (sweat gland; e–l), infiltrated by IL-3R–expressing pDCs (m–p). The specificity of the immunostainings was demonstrated using isotype match controls (a–d). ×400. (C) Immunofluorescence in 6-μm serial sections fixed in acetone showing adjacent ITAC/CXCL11 expression to that of SDF-1/CXCL12 by epithelial cells in tight contact with blood vessels in epithelial crypt of tonsils (d and g) and in sweat gland of both normal (e and h) and psoriatic (f and i) skin. The specificity of the immunostainings was demonstrated using isotype match controls (a–c). ×400. All of these observations were reproduced on more than three independent specimens.
Figure 5.
Figure 5.
Mig/CXCL9 and ITAC/CXCL11 expression in blood vessels of T cell area of tonsils and of inflamed epithelium, is adjacent to that of SDF-1/CXCL12 by epithelial cells and in close contact with IL-3R–expressing pDCs. (A) Immunohistochemistry in 6-μm tonsil serial sections fixed in acetone showing detection of Mig/CXCL9 by endothelial cells in the T cell area (b and c) and in the crypt (g) contacting epithelial cells expressing SDF-1/CXCL12 (e and f) and IL-3R+ pDCs (h and i) within the network of SDF-1/CXCL12+ epithelial cells. Isotype match controls were performed (a, the T cell area; d, the epithelial crypt). a–c, ×200; d–f, ×100; g–i, ×400. (B) Immunohistochemistry in 6-μm serial sections fixed in acetone from normal skin, psoriatic lesion, and biopsies of verrucae vulgaris and molluscum contagiosum showing Mig/CXCL9 (e–h) expression in lesions by cells contacting CD105+ blood vessels (i–l) and epithelial sites of constitutive SDF-1/CXCL12 expression (sweat gland; e–l), infiltrated by IL-3R–expressing pDCs (m–p). The specificity of the immunostainings was demonstrated using isotype match controls (a–d). ×400. (C) Immunofluorescence in 6-μm serial sections fixed in acetone showing adjacent ITAC/CXCL11 expression to that of SDF-1/CXCL12 by epithelial cells in tight contact with blood vessels in epithelial crypt of tonsils (d and g) and in sweat gland of both normal (e and h) and psoriatic (f and i) skin. The specificity of the immunostainings was demonstrated using isotype match controls (a–c). ×400. All of these observations were reproduced on more than three independent specimens.
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