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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 Treg subsets have undergone excessive proliferation. Sorted Treg subsets from pooled spleen and lymph node cells were analyzed for their TREC content. Shown is the TREC number per 1,000 cells of the indicated subsets as mean ± SD of three parallel samples from one representative out of six independent measurements. Significance (*, P < 0.05) was computed from the six means. The average TREC number per 1,000 cells in CD4+CD8− thymocytes (“high control”) and cultured Th1 cells (“low control”) was 80 and 1, respectively (not depicted).
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fig3: αE-expressing Treg subsets have undergone excessive proliferation. Sorted Treg subsets from pooled spleen and lymph node cells were analyzed for their TREC content. Shown is the TREC number per 1,000 cells of the indicated subsets as mean ± SD of three parallel samples from one representative out of six independent measurements. Significance (*, P < 0.05) was computed from the six means. The average TREC number per 1,000 cells in CD4+CD8− thymocytes (“high control”) and cultured Th1 cells (“low control”) was 80 and 1, respectively (not depicted).

Mentions: The expression profiles demonstrate developmental heterogeneity among the Treg subsets and suggest that αE+ cells, in contrast with CD25 single positive cells, might be induced or expanded in response to antigenic stimulation. The latter hypothesis was tested by analysis of the TREC number, which is an indicator of the proliferative history of T cells: naive T cells without any antigen encounter and only low homeostatic proliferation display a high TREC content, whereas the frequency of excision circle positive cells is strongly reduced in subsets that have undergone excessive proliferation (24). As shown in Fig. 3, CD25 single positive cells contained a relatively high TREC number, comparable to αE−CD25− control cells. However, αE+CD25+ and especially αE single positive cells showed significantly lower TREC numbers, indicating that they have undergone repetitive cell divisions.


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 Treg subsets have undergone excessive proliferation. Sorted Treg subsets from pooled spleen and lymph node cells were analyzed for their TREC content. Shown is the TREC number per 1,000 cells of the indicated subsets as mean ± SD of three parallel samples from one representative out of six independent measurements. Significance (*, P < 0.05) was computed from the six means. The average TREC number per 1,000 cells in CD4+CD8− thymocytes (“high control”) and cultured Th1 cells (“low control”) was 80 and 1, respectively (not depicted).
© Copyright Policy
Related In: Results  -  Collection

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

fig3: αE-expressing Treg subsets have undergone excessive proliferation. Sorted Treg subsets from pooled spleen and lymph node cells were analyzed for their TREC content. Shown is the TREC number per 1,000 cells of the indicated subsets as mean ± SD of three parallel samples from one representative out of six independent measurements. Significance (*, P < 0.05) was computed from the six means. The average TREC number per 1,000 cells in CD4+CD8− thymocytes (“high control”) and cultured Th1 cells (“low control”) was 80 and 1, respectively (not depicted).
Mentions: The expression profiles demonstrate developmental heterogeneity among the Treg subsets and suggest that αE+ cells, in contrast with CD25 single positive cells, might be induced or expanded in response to antigenic stimulation. The latter hypothesis was tested by analysis of the TREC number, which is an indicator of the proliferative history of T cells: naive T cells without any antigen encounter and only low homeostatic proliferation display a high TREC content, whereas the frequency of excision circle positive cells is strongly reduced in subsets that have undergone excessive proliferation (24). As shown in Fig. 3, CD25 single positive cells contained a relatively high TREC number, comparable to αE−CD25− control cells. However, αE+CD25+ and especially αE single positive cells showed significantly lower TREC numbers, indicating that they have undergone repetitive cell divisions.

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