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Lymph node stromal cells acquire peptide-MHCII complexes from dendritic cells and induce antigen-specific CD4⁺ T cell tolerance.

Dubrot J, Duraes FV, Potin L, Capotosti F, Brighouse D, Suter T, LeibundGut-Landmann S, Garbi N, Reith W, Swartz MA, Hugues S - J. Exp. Med. (2014)

Bottom Line: Although LNSCs express MHCII, it is unknown whether they can also impact CD4(+) T cell functions.We show that the promoter IV (pIV) of class II transactivator (CIITA), the master regulator of MHCII expression, controls endogenous MHCII expression by LNSCs.Our data reveals a novel, alternative mechanism where LN-resident stromal cells tolerize CD4(+) T cells through the presentation of self-antigens via transferred peptide-MHCII complexes of DC origin.

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Affiliation: Department of Pathology and Immunology, University of Geneva Medical School, 1211 Geneva, Switzerland.

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DCs transfer of MHCII molecules to LNSCs in vivo. (A and B) Frequencies of resident (CD11chiMHCIIint) and migratory (CD11intMHCIIhi) DC populations (A), and MHCII expression on LNSCs (B), in LN from WT and K14-VEGFR3-Ig (TG) mice. Graphs show MHCII MFI on LEC, BEC, and FRC from WT and TG mice. Each symbol represents an individual mouse. (C and D) A 1:1 acetone-butyl phthalate mixture was applied or not in the skin of pIV−/− mice. Frequencies of resident and migratory DC populations in the draining LNs 1 d after CH (C). MHC-II levels in LEC, BEC, and FRC 0, 24, and 48 h after CH (D). Graphs show MHCII MFI on LEC, BEC, and FRC. (A–D) Data are representative of at least 2 independent experiments with minimum 3 mice per group. *, P < 0.05; **, P < 0.01. Error bars depict mean ± SEM.
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fig4: DCs transfer of MHCII molecules to LNSCs in vivo. (A and B) Frequencies of resident (CD11chiMHCIIint) and migratory (CD11intMHCIIhi) DC populations (A), and MHCII expression on LNSCs (B), in LN from WT and K14-VEGFR3-Ig (TG) mice. Graphs show MHCII MFI on LEC, BEC, and FRC from WT and TG mice. Each symbol represents an individual mouse. (C and D) A 1:1 acetone-butyl phthalate mixture was applied or not in the skin of pIV−/− mice. Frequencies of resident and migratory DC populations in the draining LNs 1 d after CH (C). MHC-II levels in LEC, BEC, and FRC 0, 24, and 48 h after CH (D). Graphs show MHCII MFI on LEC, BEC, and FRC. (A–D) Data are representative of at least 2 independent experiments with minimum 3 mice per group. *, P < 0.05; **, P < 0.01. Error bars depict mean ± SEM.

Mentions: To definitively demonstrate that LNSCs acquire MHCII molecules from DCs in vivo, we manipulated the numbers of DCs in LNs and analyzed the impact on MHCII expression by LNSCs. First, K14-VEGFR3-Ig transgenic mice (Mäkinen et al., 2001) that are deficient in skin-afferent lymphatics, resulting in an abrogation of skin DC homing to LN (Fig. 4 A), exhibited reduced MHCII expression in LECs, BECs, and FRCs compared with WT cells (Fig. 4 B). Next, we used a model of contact hypersensitivity (CH) to enhance migration of skin DCs to draining LNs (Fig. 4 C; Thomas et al., 2012). To avoid endogenous MHCII up-regulation by LNSCs due to skin inflammation and thereby quantify only DC transfer–mediated MHCII expression, CH was induced in pIV−/− mice. Expression of MHCII was significantly increased at 24 and 48 h in LEC and BEC populations and at 48 h in FRCs after CH (Fig. 4 D). Altogether, our data demonstrated that LNSCs acquire MHCII molecules from DCs in vivo and that the intensity of MHCII expression by LNSCs proportionally correlates with the numbers of DCs in LNs.


Lymph node stromal cells acquire peptide-MHCII complexes from dendritic cells and induce antigen-specific CD4⁺ T cell tolerance.

Dubrot J, Duraes FV, Potin L, Capotosti F, Brighouse D, Suter T, LeibundGut-Landmann S, Garbi N, Reith W, Swartz MA, Hugues S - J. Exp. Med. (2014)

DCs transfer of MHCII molecules to LNSCs in vivo. (A and B) Frequencies of resident (CD11chiMHCIIint) and migratory (CD11intMHCIIhi) DC populations (A), and MHCII expression on LNSCs (B), in LN from WT and K14-VEGFR3-Ig (TG) mice. Graphs show MHCII MFI on LEC, BEC, and FRC from WT and TG mice. Each symbol represents an individual mouse. (C and D) A 1:1 acetone-butyl phthalate mixture was applied or not in the skin of pIV−/− mice. Frequencies of resident and migratory DC populations in the draining LNs 1 d after CH (C). MHC-II levels in LEC, BEC, and FRC 0, 24, and 48 h after CH (D). Graphs show MHCII MFI on LEC, BEC, and FRC. (A–D) Data are representative of at least 2 independent experiments with minimum 3 mice per group. *, P < 0.05; **, P < 0.01. Error bars depict mean ± SEM.
© Copyright Policy - openaccess
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC4042642&req=5

fig4: DCs transfer of MHCII molecules to LNSCs in vivo. (A and B) Frequencies of resident (CD11chiMHCIIint) and migratory (CD11intMHCIIhi) DC populations (A), and MHCII expression on LNSCs (B), in LN from WT and K14-VEGFR3-Ig (TG) mice. Graphs show MHCII MFI on LEC, BEC, and FRC from WT and TG mice. Each symbol represents an individual mouse. (C and D) A 1:1 acetone-butyl phthalate mixture was applied or not in the skin of pIV−/− mice. Frequencies of resident and migratory DC populations in the draining LNs 1 d after CH (C). MHC-II levels in LEC, BEC, and FRC 0, 24, and 48 h after CH (D). Graphs show MHCII MFI on LEC, BEC, and FRC. (A–D) Data are representative of at least 2 independent experiments with minimum 3 mice per group. *, P < 0.05; **, P < 0.01. Error bars depict mean ± SEM.
Mentions: To definitively demonstrate that LNSCs acquire MHCII molecules from DCs in vivo, we manipulated the numbers of DCs in LNs and analyzed the impact on MHCII expression by LNSCs. First, K14-VEGFR3-Ig transgenic mice (Mäkinen et al., 2001) that are deficient in skin-afferent lymphatics, resulting in an abrogation of skin DC homing to LN (Fig. 4 A), exhibited reduced MHCII expression in LECs, BECs, and FRCs compared with WT cells (Fig. 4 B). Next, we used a model of contact hypersensitivity (CH) to enhance migration of skin DCs to draining LNs (Fig. 4 C; Thomas et al., 2012). To avoid endogenous MHCII up-regulation by LNSCs due to skin inflammation and thereby quantify only DC transfer–mediated MHCII expression, CH was induced in pIV−/− mice. Expression of MHCII was significantly increased at 24 and 48 h in LEC and BEC populations and at 48 h in FRCs after CH (Fig. 4 D). Altogether, our data demonstrated that LNSCs acquire MHCII molecules from DCs in vivo and that the intensity of MHCII expression by LNSCs proportionally correlates with the numbers of DCs in LNs.

Bottom Line: Although LNSCs express MHCII, it is unknown whether they can also impact CD4(+) T cell functions.We show that the promoter IV (pIV) of class II transactivator (CIITA), the master regulator of MHCII expression, controls endogenous MHCII expression by LNSCs.Our data reveals a novel, alternative mechanism where LN-resident stromal cells tolerize CD4(+) T cells through the presentation of self-antigens via transferred peptide-MHCII complexes of DC origin.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pathology and Immunology, University of Geneva Medical School, 1211 Geneva, Switzerland.

Show MeSH
Related in: MedlinePlus