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Developmental stage, phenotype, and migration distinguish naive- and effector/memory-like CD4+ regulatory T cells.

Huehn J, Siegmund K, Lehmann JC, Siewert C, Haubold U, Feuerer M, Debes GF, Lauber J, Frey O, Przybylski GK, Niesner U, de la Rosa M, Schmidt CA, Bräuer R, Buer J, Scheffold A, Hamann A - J. Exp. Med. (2004)

Bottom Line: We reported previously that the integrin alphaEbeta7 discriminates distinct subsets of murine CD4+ regulatory T cells.Use of this marker has now helped to unravel a fundamental dichotomy among regulatory T cells. alphaE-CD25+ cells expressed L-selectin and CCR7, enabling recirculation through lymphoid tissues.Accordingly, alphaE -expressing cells were found to be the most potent suppressors of inflammatory processes in disease models such as antigen-induced arthritis.

View Article: PubMed Central - PubMed

Affiliation: Experimentelle Rheumatologie, Medizinische Klinik, Charité, Humboldt-Universitaet, Schumannstr. 21/22, 10117 Berlin, Germany. Huehn@drfz.de

ABSTRACT
Regulatory T cells (Tregs) fulfill a central role in immune regulation. We reported previously that the integrin alphaEbeta7 discriminates distinct subsets of murine CD4+ regulatory T cells. Use of this marker has now helped to unravel a fundamental dichotomy among regulatory T cells. alphaE-CD25+ cells expressed L-selectin and CCR7, enabling recirculation through lymphoid tissues. In contrast, alphaE -positive subsets (CD25+ and CD25-) displayed an effector/memory phenotype expressing high levels of E/P-selectin-binding ligands, multiple adhesion molecules as well as receptors for inflammatory chemokines, allowing efficient migration into inflamed sites. Accordingly, alphaE -expressing cells were found to be the most potent suppressors of inflammatory processes in disease models such as antigen-induced arthritis.

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αE-expressing subsets show the strongest suppression of inflammatory reactions in antigen-induced arthritis. (A and B) mBSA-immunized C57Bl6 mice received 105 FACS®-sorted and polyclonally preactivated cells 24 h before intraarticular mBSA injection (αE+CD25+, n = 4; αE+CD25−, n = 4; αE−CD25+, n = 11; αE−CD25−, n = 11; and PBS alone, n = 10). (A) The progression of arthritis was monitored by the measurement of knee joint swelling (mean ± SD; one representative out of two independent experiments). αE+CD25+ and αE+CD25− cells showed a higher suppressive capacity than CD25 single positive cells (P < 0.01 and P = 0.085, respectively). (B) At day 14, tissues were taken for histological examination. The final arthritis score was evaluated for each animal (mean ± SEM; one representative out of two independent experiments). αE+CD25+ cells showed a significantly lower arthritis score than CD25 single positive cells (*, P < 0.05). (C) Radioactively labeled T cell subsets were injected i.v. in mBSA-immunized mice that had received an intraarticular mBSA injection 4 d before the homing experiment. Recovered radioactivity from the inflamed knee was determined after 24 h using a γ-counter. Percentage of total recovered radioactivity is shown (n = 6; mean ± SD; one representative out of two independent experiments). αE+CD25+ and αE+CD25− cells showed a significantly higher migration into the inflamed knee joint compared with CD25 single positive cells (*, P < 0.05).
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fig6: αE-expressing subsets show the strongest suppression of inflammatory reactions in antigen-induced arthritis. (A and B) mBSA-immunized C57Bl6 mice received 105 FACS®-sorted and polyclonally preactivated cells 24 h before intraarticular mBSA injection (αE+CD25+, n = 4; αE+CD25−, n = 4; αE−CD25+, n = 11; αE−CD25−, n = 11; and PBS alone, n = 10). (A) The progression of arthritis was monitored by the measurement of knee joint swelling (mean ± SD; one representative out of two independent experiments). αE+CD25+ and αE+CD25− cells showed a higher suppressive capacity than CD25 single positive cells (P < 0.01 and P = 0.085, respectively). (B) At day 14, tissues were taken for histological examination. The final arthritis score was evaluated for each animal (mean ± SEM; one representative out of two independent experiments). αE+CD25+ cells showed a significantly lower arthritis score than CD25 single positive cells (*, P < 0.05). (C) Radioactively labeled T cell subsets were injected i.v. in mBSA-immunized mice that had received an intraarticular mBSA injection 4 d before the homing experiment. Recovered radioactivity from the inflamed knee was determined after 24 h using a γ-counter. Percentage of total recovered radioactivity is shown (n = 6; mean ± SD; one representative out of two independent experiments). αE+CD25+ and αE+CD25− cells showed a significantly higher migration into the inflamed knee joint compared with CD25 single positive cells (*, P < 0.05).

Mentions: The measurement of knee joint swelling at various time points revealed that only αE-expressing Treg subsets could efficiently inhibit the acute inflammation (Fig. 6 A), with especially the αE+CD25+ cells displaying a high suppressive capacity. Adoptive transfer of CD25 single positive cells had no curative effect on knee joint swelling, which was similar to mice receiving control cells (αE−CD25−) or PBS only. Histological examinations of knee joints in the chronic phase of arthritis revealed that mice receiving αE-expressing Treg subsets had reduced mononuclear infiltrates, whereas marked inflammatory signs were observed in mice adoptively transferred with CD25 single positive cells (Fig. 6 B and Fig. S4 available at http://www.jem.org/cgi/content/full/jem.20031562/DC1). Lack of suppression by CD25 single positive cells and antiinflammatory activity of αE-expressing Tregs was also found in a transgenic, Th1-mediated footpad delayed-type hypersensitivity model (unpublished data).


Developmental stage, phenotype, and migration distinguish naive- and effector/memory-like CD4+ regulatory T cells.

Huehn J, Siegmund K, Lehmann JC, Siewert C, Haubold U, Feuerer M, Debes GF, Lauber J, Frey O, Przybylski GK, Niesner U, de la Rosa M, Schmidt CA, Bräuer R, Buer J, Scheffold A, Hamann A - J. Exp. Med. (2004)

αE-expressing subsets show the strongest suppression of inflammatory reactions in antigen-induced arthritis. (A and B) mBSA-immunized C57Bl6 mice received 105 FACS®-sorted and polyclonally preactivated cells 24 h before intraarticular mBSA injection (αE+CD25+, n = 4; αE+CD25−, n = 4; αE−CD25+, n = 11; αE−CD25−, n = 11; and PBS alone, n = 10). (A) The progression of arthritis was monitored by the measurement of knee joint swelling (mean ± SD; one representative out of two independent experiments). αE+CD25+ and αE+CD25− cells showed a higher suppressive capacity than CD25 single positive cells (P < 0.01 and P = 0.085, respectively). (B) At day 14, tissues were taken for histological examination. The final arthritis score was evaluated for each animal (mean ± SEM; one representative out of two independent experiments). αE+CD25+ cells showed a significantly lower arthritis score than CD25 single positive cells (*, P < 0.05). (C) Radioactively labeled T cell subsets were injected i.v. in mBSA-immunized mice that had received an intraarticular mBSA injection 4 d before the homing experiment. Recovered radioactivity from the inflamed knee was determined after 24 h using a γ-counter. Percentage of total recovered radioactivity is shown (n = 6; mean ± SD; one representative out of two independent experiments). αE+CD25+ and αE+CD25− cells showed a significantly higher migration into the inflamed knee joint compared with CD25 single positive cells (*, P < 0.05).
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Related In: Results  -  Collection

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fig6: αE-expressing subsets show the strongest suppression of inflammatory reactions in antigen-induced arthritis. (A and B) mBSA-immunized C57Bl6 mice received 105 FACS®-sorted and polyclonally preactivated cells 24 h before intraarticular mBSA injection (αE+CD25+, n = 4; αE+CD25−, n = 4; αE−CD25+, n = 11; αE−CD25−, n = 11; and PBS alone, n = 10). (A) The progression of arthritis was monitored by the measurement of knee joint swelling (mean ± SD; one representative out of two independent experiments). αE+CD25+ and αE+CD25− cells showed a higher suppressive capacity than CD25 single positive cells (P < 0.01 and P = 0.085, respectively). (B) At day 14, tissues were taken for histological examination. The final arthritis score was evaluated for each animal (mean ± SEM; one representative out of two independent experiments). αE+CD25+ cells showed a significantly lower arthritis score than CD25 single positive cells (*, P < 0.05). (C) Radioactively labeled T cell subsets were injected i.v. in mBSA-immunized mice that had received an intraarticular mBSA injection 4 d before the homing experiment. Recovered radioactivity from the inflamed knee was determined after 24 h using a γ-counter. Percentage of total recovered radioactivity is shown (n = 6; mean ± SD; one representative out of two independent experiments). αE+CD25+ and αE+CD25− cells showed a significantly higher migration into the inflamed knee joint compared with CD25 single positive cells (*, P < 0.05).
Mentions: The measurement of knee joint swelling at various time points revealed that only αE-expressing Treg subsets could efficiently inhibit the acute inflammation (Fig. 6 A), with especially the αE+CD25+ cells displaying a high suppressive capacity. Adoptive transfer of CD25 single positive cells had no curative effect on knee joint swelling, which was similar to mice receiving control cells (αE−CD25−) or PBS only. Histological examinations of knee joints in the chronic phase of arthritis revealed that mice receiving αE-expressing Treg subsets had reduced mononuclear infiltrates, whereas marked inflammatory signs were observed in mice adoptively transferred with CD25 single positive cells (Fig. 6 B and Fig. S4 available at http://www.jem.org/cgi/content/full/jem.20031562/DC1). Lack of suppression by CD25 single positive cells and antiinflammatory activity of αE-expressing Tregs was also found in a transgenic, Th1-mediated footpad delayed-type hypersensitivity model (unpublished data).

Bottom Line: We reported previously that the integrin alphaEbeta7 discriminates distinct subsets of murine CD4+ regulatory T cells.Use of this marker has now helped to unravel a fundamental dichotomy among regulatory T cells. alphaE-CD25+ cells expressed L-selectin and CCR7, enabling recirculation through lymphoid tissues.Accordingly, alphaE -expressing cells were found to be the most potent suppressors of inflammatory processes in disease models such as antigen-induced arthritis.

View Article: PubMed Central - PubMed

Affiliation: Experimentelle Rheumatologie, Medizinische Klinik, Charité, Humboldt-Universitaet, Schumannstr. 21/22, 10117 Berlin, Germany. Huehn@drfz.de

ABSTRACT
Regulatory T cells (Tregs) fulfill a central role in immune regulation. We reported previously that the integrin alphaEbeta7 discriminates distinct subsets of murine CD4+ regulatory T cells. Use of this marker has now helped to unravel a fundamental dichotomy among regulatory T cells. alphaE-CD25+ cells expressed L-selectin and CCR7, enabling recirculation through lymphoid tissues. In contrast, alphaE -positive subsets (CD25+ and CD25-) displayed an effector/memory phenotype expressing high levels of E/P-selectin-binding ligands, multiple adhesion molecules as well as receptors for inflammatory chemokines, allowing efficient migration into inflamed sites. Accordingly, alphaE -expressing cells were found to be the most potent suppressors of inflammatory processes in disease models such as antigen-induced arthritis.

Show MeSH
Related in: MedlinePlus