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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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Phenotyping for effector/memory markers as well as adhesion molecules unravels a high degree of heterogeneity among Treg subsets. FACS® analysis of pooled spleen and lymph node cells shows the expression of several effector/memory markers and adhesion molecules on indicated CD4+ T cell subsets. Representative histogram plots from three independent experiments were selected showing stainings (gray) plus isotype controls (white). The graphs summarize data from one representative experiment and show frequency or mean fluorescence intensity of the indicated subsets as mean ± SD from three independently analyzed animals.
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fig2: Phenotyping for effector/memory markers as well as adhesion molecules unravels a high degree of heterogeneity among Treg subsets. FACS® analysis of pooled spleen and lymph node cells shows the expression of several effector/memory markers and adhesion molecules on indicated CD4+ T cell subsets. Representative histogram plots from three independent experiments were selected showing stainings (gray) plus isotype controls (white). The graphs summarize data from one representative experiment and show frequency or mean fluorescence intensity of the indicated subsets as mean ± SD from three independently analyzed animals.

Mentions: To confirm the differences observed by gene profiling, we performed quantitative RT-PCR (Table SI available at http://www.jem.org/cgi/content/full/jem.20031562/DC1) and surface stainings on CD4+ T cells for several molecules used as markers to discriminate naive and antigen-experienced T cells, or known as costimulatory and adhesion molecules involved in lymphocyte trafficking (Fig. 2). CD45RB expression was reduced in all three Treg subsets in comparison with the predominantly naive control cells (αE−CD25−), as reported previously (18). However, the αE-expressing subsets and especially αE+CD25− cells showed significantly lower CD45RB levels than CD25 single positive cells (P < 0.01). This pattern (a naivelike phenotype of CD25 single positive and an effector/memory-like phenotype of αE-expressing cells) was even more obvious for two other well-established markers, CD44 and L-selectin. Additionally, a large number of further adhesion and costimulatory molecules known to be associated with an effector/memory status, such as CD54 (intercellular adhesion molecule 1), ICOS, β1-integrin (CD29), or LFA-1, were expressed at higher levels or on a greater fraction of cells among the αE+ subsets. In general, αE+CD25+ cells showed intermediate expression levels (CD44, CD54, and LFA-1) or a more heterogeneous distribution (CD45RB, L-selectin, ICOS, and β1-integrin). In contrast, another differentially expressed activation marker, CD69, displayed the highest frequency among the αE+CD25+ subset.


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)

Phenotyping for effector/memory markers as well as adhesion molecules unravels a high degree of heterogeneity among Treg subsets. FACS® analysis of pooled spleen and lymph node cells shows the expression of several effector/memory markers and adhesion molecules on indicated CD4+ T cell subsets. Representative histogram plots from three independent experiments were selected showing stainings (gray) plus isotype controls (white). The graphs summarize data from one representative experiment and show frequency or mean fluorescence intensity of the indicated subsets as mean ± SD from three independently analyzed animals.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2211798&req=5

fig2: Phenotyping for effector/memory markers as well as adhesion molecules unravels a high degree of heterogeneity among Treg subsets. FACS® analysis of pooled spleen and lymph node cells shows the expression of several effector/memory markers and adhesion molecules on indicated CD4+ T cell subsets. Representative histogram plots from three independent experiments were selected showing stainings (gray) plus isotype controls (white). The graphs summarize data from one representative experiment and show frequency or mean fluorescence intensity of the indicated subsets as mean ± SD from three independently analyzed animals.
Mentions: To confirm the differences observed by gene profiling, we performed quantitative RT-PCR (Table SI available at http://www.jem.org/cgi/content/full/jem.20031562/DC1) and surface stainings on CD4+ T cells for several molecules used as markers to discriminate naive and antigen-experienced T cells, or known as costimulatory and adhesion molecules involved in lymphocyte trafficking (Fig. 2). CD45RB expression was reduced in all three Treg subsets in comparison with the predominantly naive control cells (αE−CD25−), as reported previously (18). However, the αE-expressing subsets and especially αE+CD25− cells showed significantly lower CD45RB levels than CD25 single positive cells (P < 0.01). This pattern (a naivelike phenotype of CD25 single positive and an effector/memory-like phenotype of αE-expressing cells) was even more obvious for two other well-established markers, CD44 and L-selectin. Additionally, a large number of further adhesion and costimulatory molecules known to be associated with an effector/memory status, such as CD54 (intercellular adhesion molecule 1), ICOS, β1-integrin (CD29), or LFA-1, were expressed at higher levels or on a greater fraction of cells among the αE+ subsets. In general, αE+CD25+ cells showed intermediate expression levels (CD44, CD54, and LFA-1) or a more heterogeneous distribution (CD45RB, L-selectin, ICOS, and β1-integrin). In contrast, another differentially expressed activation marker, CD69, displayed the highest frequency among the αE+CD25+ subset.

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