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Accumulation of immature Langerhans cells in human lymph nodes draining chronically inflamed skin.

Geissmann F, Dieu-Nosjean MC, Dezutter C, Valladeau J, Kayal S, Leborgne M, Brousse N, Saeland S, Davoust J - J. Exp. Med. (2002)

Bottom Line: This indicates that LC migration and maturation can be independently regulated events.We suggest that during DL, inflammatory stimuli in the skin increase the migration of LCs to the lymph node but without associated maturation.Immature LCs might regulate immune responses during chronic inflammation.

View Article: PubMed Central - PubMed

Affiliation: Service d'Anatomie Pathologique, IFR Necker-Enfants Malades, 75015 Paris, France. geissman@necker.fr

ABSTRACT
The coordinated migration and maturation of dendritic cells (DCs) such as intraepithelial Langerhans cells (LCs) is considered critical for T cell priming in response to inflammation in the periphery. However, little is known about the role of inflammatory mediators for LC maturation and recruitment to lymph nodes in vivo. Here we show in human dermatopathic lymphadenitis (DL), which features an expanded population of LCs in one draining lymph node associated with inflammatory lesions in its tributary skin area, that the Langerin/CD207(+) LCs constitute a predominant population of immature DCs, which express CD1a, and CD68, but not CD83, CD86, and DC-lysosomal-associated membrane protein (LAMP)/CD208. Using LC-type cells generated in vitro in the presence of transforming growth factor (TGF)-beta1, we further found that tumor necrosis factor (TNF)-alpha, as a prototype proinflammatory factor, and a variety of inflammatory stimuli and bacterial products, increase Langerin expression and Langerin dependent Birbeck granules formation in cell which nevertheless lack costimulatory molecules, DC-LAMP/CD208 and potent T cell stimulatory activity but express CCR7 and respond to the lymph node homing chemokines CCL19 and CCL21. This indicates that LC migration and maturation can be independently regulated events. We suggest that during DL, inflammatory stimuli in the skin increase the migration of LCs to the lymph node but without associated maturation. Immature LCs might regulate immune responses during chronic inflammation.

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LPS and bacteria induce the maturation of DCi but not LC-type cells. Interstitial-type and LC-type DC were cultured for 5–6 d as indicated in Materials and Methods and incubated with either LPS, heat-inactivated E. coli, or BCG-GFP. (A and B) Coculture with LPS induces the maturation of interstitial type, but not LC-type DCs. LC-type (A) and (B) DCi treated with LPS were fixed, permeabilized, stained with FITC-conjugated anti–HLA-DR antibody and anti-Langerin antibody revealed with anti–mouse Cy3 (in red), and analyzed by confocal microscopy. Original magnification: ×400. (C–E) Coculture with heat inactivated E. coli does not induce the maturation of LC-type DC. LC-type DCs were cultured for 40 h in the presence of Texas-red conjugated heat-inactivated E. coli at a 50/1 ratio (C-E) or LcCD40L (F) and then collected, washed, fixed, permeabilized and stained with either FITC-conjugated anti-Langerin antibody (C and D) or FITC-conjugated anti–HLA-DR antibody and anti-Langerin antibody revealed with anti–mouse Cy5 (in blue) (E and F), and analyzed by confocal microscopy. Coculture of DCi induced their maturation (unpublished data). Panel G LC-type DC were cultured for 36 h in the presence of BCG-GFP and then collected, washed, fixed, permeabilized, stained with PE-conjugated anti-HLA-DR antibody and anti-Langerin antibody revealed with anti mouse Cy5 (in blue), and analyzed by confocal microscopy. Arrow indicates a Langerin− DRhi DC and arrowheads Langerin+ DRlo DCs. Coculture of DCi with BCG-GFP induced their maturation (unpublished data). Bar = 10 μm, unless otherwise indicated.
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fig6: LPS and bacteria induce the maturation of DCi but not LC-type cells. Interstitial-type and LC-type DC were cultured for 5–6 d as indicated in Materials and Methods and incubated with either LPS, heat-inactivated E. coli, or BCG-GFP. (A and B) Coculture with LPS induces the maturation of interstitial type, but not LC-type DCs. LC-type (A) and (B) DCi treated with LPS were fixed, permeabilized, stained with FITC-conjugated anti–HLA-DR antibody and anti-Langerin antibody revealed with anti–mouse Cy3 (in red), and analyzed by confocal microscopy. Original magnification: ×400. (C–E) Coculture with heat inactivated E. coli does not induce the maturation of LC-type DC. LC-type DCs were cultured for 40 h in the presence of Texas-red conjugated heat-inactivated E. coli at a 50/1 ratio (C-E) or LcCD40L (F) and then collected, washed, fixed, permeabilized and stained with either FITC-conjugated anti-Langerin antibody (C and D) or FITC-conjugated anti–HLA-DR antibody and anti-Langerin antibody revealed with anti–mouse Cy5 (in blue) (E and F), and analyzed by confocal microscopy. Coculture of DCi induced their maturation (unpublished data). Panel G LC-type DC were cultured for 36 h in the presence of BCG-GFP and then collected, washed, fixed, permeabilized, stained with PE-conjugated anti-HLA-DR antibody and anti-Langerin antibody revealed with anti mouse Cy5 (in blue), and analyzed by confocal microscopy. Arrow indicates a Langerin− DRhi DC and arrowheads Langerin+ DRlo DCs. Coculture of DCi with BCG-GFP induced their maturation (unpublished data). Bar = 10 μm, unless otherwise indicated.

Mentions: We further investigated the effects of exposure to bacterial products, likely to occur in an inflammatory skin, mucosa, or lung, on the maturation of monocyte-derived LCs. Exposure to LPS was found to induce Langerin expression on LC-type DCs (Fig. 6 A). This induction resulted in a twofold increase in Langerin+ cells (from 28 to 52% of cells as counted on wide-field micrographs) but LPS induced neither DC–LAMP expression, nor the translocation of MHC class II molecules to the cell surface (Fig. 6 A). In contrast to LC-type cells, LPS induced the maturation of DCi used as controls without significant induction of Langerin expression (Fig. 6 B).


Accumulation of immature Langerhans cells in human lymph nodes draining chronically inflamed skin.

Geissmann F, Dieu-Nosjean MC, Dezutter C, Valladeau J, Kayal S, Leborgne M, Brousse N, Saeland S, Davoust J - J. Exp. Med. (2002)

LPS and bacteria induce the maturation of DCi but not LC-type cells. Interstitial-type and LC-type DC were cultured for 5–6 d as indicated in Materials and Methods and incubated with either LPS, heat-inactivated E. coli, or BCG-GFP. (A and B) Coculture with LPS induces the maturation of interstitial type, but not LC-type DCs. LC-type (A) and (B) DCi treated with LPS were fixed, permeabilized, stained with FITC-conjugated anti–HLA-DR antibody and anti-Langerin antibody revealed with anti–mouse Cy3 (in red), and analyzed by confocal microscopy. Original magnification: ×400. (C–E) Coculture with heat inactivated E. coli does not induce the maturation of LC-type DC. LC-type DCs were cultured for 40 h in the presence of Texas-red conjugated heat-inactivated E. coli at a 50/1 ratio (C-E) or LcCD40L (F) and then collected, washed, fixed, permeabilized and stained with either FITC-conjugated anti-Langerin antibody (C and D) or FITC-conjugated anti–HLA-DR antibody and anti-Langerin antibody revealed with anti–mouse Cy5 (in blue) (E and F), and analyzed by confocal microscopy. Coculture of DCi induced their maturation (unpublished data). Panel G LC-type DC were cultured for 36 h in the presence of BCG-GFP and then collected, washed, fixed, permeabilized, stained with PE-conjugated anti-HLA-DR antibody and anti-Langerin antibody revealed with anti mouse Cy5 (in blue), and analyzed by confocal microscopy. Arrow indicates a Langerin− DRhi DC and arrowheads Langerin+ DRlo DCs. Coculture of DCi with BCG-GFP induced their maturation (unpublished data). Bar = 10 μm, unless otherwise indicated.
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Related In: Results  -  Collection

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fig6: LPS and bacteria induce the maturation of DCi but not LC-type cells. Interstitial-type and LC-type DC were cultured for 5–6 d as indicated in Materials and Methods and incubated with either LPS, heat-inactivated E. coli, or BCG-GFP. (A and B) Coculture with LPS induces the maturation of interstitial type, but not LC-type DCs. LC-type (A) and (B) DCi treated with LPS were fixed, permeabilized, stained with FITC-conjugated anti–HLA-DR antibody and anti-Langerin antibody revealed with anti–mouse Cy3 (in red), and analyzed by confocal microscopy. Original magnification: ×400. (C–E) Coculture with heat inactivated E. coli does not induce the maturation of LC-type DC. LC-type DCs were cultured for 40 h in the presence of Texas-red conjugated heat-inactivated E. coli at a 50/1 ratio (C-E) or LcCD40L (F) and then collected, washed, fixed, permeabilized and stained with either FITC-conjugated anti-Langerin antibody (C and D) or FITC-conjugated anti–HLA-DR antibody and anti-Langerin antibody revealed with anti–mouse Cy5 (in blue) (E and F), and analyzed by confocal microscopy. Coculture of DCi induced their maturation (unpublished data). Panel G LC-type DC were cultured for 36 h in the presence of BCG-GFP and then collected, washed, fixed, permeabilized, stained with PE-conjugated anti-HLA-DR antibody and anti-Langerin antibody revealed with anti mouse Cy5 (in blue), and analyzed by confocal microscopy. Arrow indicates a Langerin− DRhi DC and arrowheads Langerin+ DRlo DCs. Coculture of DCi with BCG-GFP induced their maturation (unpublished data). Bar = 10 μm, unless otherwise indicated.
Mentions: We further investigated the effects of exposure to bacterial products, likely to occur in an inflammatory skin, mucosa, or lung, on the maturation of monocyte-derived LCs. Exposure to LPS was found to induce Langerin expression on LC-type DCs (Fig. 6 A). This induction resulted in a twofold increase in Langerin+ cells (from 28 to 52% of cells as counted on wide-field micrographs) but LPS induced neither DC–LAMP expression, nor the translocation of MHC class II molecules to the cell surface (Fig. 6 A). In contrast to LC-type cells, LPS induced the maturation of DCi used as controls without significant induction of Langerin expression (Fig. 6 B).

Bottom Line: This indicates that LC migration and maturation can be independently regulated events.We suggest that during DL, inflammatory stimuli in the skin increase the migration of LCs to the lymph node but without associated maturation.Immature LCs might regulate immune responses during chronic inflammation.

View Article: PubMed Central - PubMed

Affiliation: Service d'Anatomie Pathologique, IFR Necker-Enfants Malades, 75015 Paris, France. geissman@necker.fr

ABSTRACT
The coordinated migration and maturation of dendritic cells (DCs) such as intraepithelial Langerhans cells (LCs) is considered critical for T cell priming in response to inflammation in the periphery. However, little is known about the role of inflammatory mediators for LC maturation and recruitment to lymph nodes in vivo. Here we show in human dermatopathic lymphadenitis (DL), which features an expanded population of LCs in one draining lymph node associated with inflammatory lesions in its tributary skin area, that the Langerin/CD207(+) LCs constitute a predominant population of immature DCs, which express CD1a, and CD68, but not CD83, CD86, and DC-lysosomal-associated membrane protein (LAMP)/CD208. Using LC-type cells generated in vitro in the presence of transforming growth factor (TGF)-beta1, we further found that tumor necrosis factor (TNF)-alpha, as a prototype proinflammatory factor, and a variety of inflammatory stimuli and bacterial products, increase Langerin expression and Langerin dependent Birbeck granules formation in cell which nevertheless lack costimulatory molecules, DC-LAMP/CD208 and potent T cell stimulatory activity but express CCR7 and respond to the lymph node homing chemokines CCL19 and CCL21. This indicates that LC migration and maturation can be independently regulated events. We suggest that during DL, inflammatory stimuli in the skin increase the migration of LCs to the lymph node but without associated maturation. Immature LCs might regulate immune responses during chronic inflammation.

Show MeSH
Related in: MedlinePlus