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Continuous activation of autoreactive CD4+ CD25+ regulatory T cells in the steady state.

Fisson S, Darrasse-Jèze G, Litvinova E, Septier F, Klatzmann D, Liblau R, Salomon BL - J. Exp. Med. (2003)

Bottom Line: In the steady state, some Treg remain quiescent and have a long lifespan, in the order of months, whereas the other Treg are dividing extensively and express multiple activation markers.After adoptive transfer, tissue-specific Treg rapidly divide and expand preferentially in lymph nodes draining their target self-antigens.These results reveal the existence of a cycling Treg subset composed of autoreactive Treg that are continuously activated by tissue self-antigens.

View Article: PubMed Central - PubMed

Affiliation: CNRS UMR 7087, Batiment CERVI, Hôpital de la Pitié-Salpêtrière, 83 Boulevard de l'Hôpital, 75013 Paris, France.

ABSTRACT
Despite a growing interest in CD4+ CD25+ regulatory T cells (Treg) that play a major role in self-tolerance and immunoregulation, fundamental parameters of the biology and homeostasis of these cells are poorly known. Here, we show that this population is composed of two Treg subsets that have distinct phenotypes and homeostasis in normal unmanipulated mice. In the steady state, some Treg remain quiescent and have a long lifespan, in the order of months, whereas the other Treg are dividing extensively and express multiple activation markers. After adoptive transfer, tissue-specific Treg rapidly divide and expand preferentially in lymph nodes draining their target self-antigens. These results reveal the existence of a cycling Treg subset composed of autoreactive Treg that are continuously activated by tissue self-antigens.

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Analysis of turnover of Treg by BrdU incorporation. BALB/c mice were treated with BrdU administered continuously for 7 d using osmotic pumps. Then, peripheral LN cells and splenocytes were analyzed for cell surface expression of CD4, CD25, and CD44, and BrdU incorporated into DNA of divided cells. Levels of BrdU incorporations were quantified on gated CD4+ CD25+ CD44high cells and CD4+ CD25+ CD44low cells in LNs and the spleen as defined in A. Background BrdU staining levels were obtained from untreated mice (B). Representative results are shown and values indicate the mean ± SD of BrdU+ cells from data from two independent experiments (seven mice). The percentage of CD25+ CD4+ T cells was not statistically different in mice receiving osmotic pump with BrdU, mice receiving osmotic pump with PBS, and unmanipulated mice. In A, CD25+ CD4+ T cells represented 8.2% of CD4+ cells.
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fig3: Analysis of turnover of Treg by BrdU incorporation. BALB/c mice were treated with BrdU administered continuously for 7 d using osmotic pumps. Then, peripheral LN cells and splenocytes were analyzed for cell surface expression of CD4, CD25, and CD44, and BrdU incorporated into DNA of divided cells. Levels of BrdU incorporations were quantified on gated CD4+ CD25+ CD44high cells and CD4+ CD25+ CD44low cells in LNs and the spleen as defined in A. Background BrdU staining levels were obtained from untreated mice (B). Representative results are shown and values indicate the mean ± SD of BrdU+ cells from data from two independent experiments (seven mice). The percentage of CD25+ CD4+ T cells was not statistically different in mice receiving osmotic pump with BrdU, mice receiving osmotic pump with PBS, and unmanipulated mice. In A, CD25+ CD4+ T cells represented 8.2% of CD4+ cells.

Mentions: To evaluate the recirculation properties, lifespan, turnover rate, and CD25 marker expression stability of the natural suppressor Treg, we transferred Treg purified from normal mice, having a diversified T cell repertoire, into unmanipulated nonlymphopenic normal Thy-1 congenic mice. We focused this study on the transfer of the CD62Lhigh Treg subset because we and others have previously demonstrated the high suppressive activity of this population in vivo (7, 32) and also because the CD4+ CD25+ CD62Lhigh cell population should contain low, if any, contamination with activated conventional CD4+ T lymphocytes, which display a CD4+ CD25+ CD62Llow phenotype (33). Experiments described below and shown in Figs. 1, 2, and 3 were all performed in the BALB/c genetic background. For all of these experiments, similar findings were observed in the C57BL/6 genetic background (unpublished data).


Continuous activation of autoreactive CD4+ CD25+ regulatory T cells in the steady state.

Fisson S, Darrasse-Jèze G, Litvinova E, Septier F, Klatzmann D, Liblau R, Salomon BL - J. Exp. Med. (2003)

Analysis of turnover of Treg by BrdU incorporation. BALB/c mice were treated with BrdU administered continuously for 7 d using osmotic pumps. Then, peripheral LN cells and splenocytes were analyzed for cell surface expression of CD4, CD25, and CD44, and BrdU incorporated into DNA of divided cells. Levels of BrdU incorporations were quantified on gated CD4+ CD25+ CD44high cells and CD4+ CD25+ CD44low cells in LNs and the spleen as defined in A. Background BrdU staining levels were obtained from untreated mice (B). Representative results are shown and values indicate the mean ± SD of BrdU+ cells from data from two independent experiments (seven mice). The percentage of CD25+ CD4+ T cells was not statistically different in mice receiving osmotic pump with BrdU, mice receiving osmotic pump with PBS, and unmanipulated mice. In A, CD25+ CD4+ T cells represented 8.2% of CD4+ cells.
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Related In: Results  -  Collection

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fig3: Analysis of turnover of Treg by BrdU incorporation. BALB/c mice were treated with BrdU administered continuously for 7 d using osmotic pumps. Then, peripheral LN cells and splenocytes were analyzed for cell surface expression of CD4, CD25, and CD44, and BrdU incorporated into DNA of divided cells. Levels of BrdU incorporations were quantified on gated CD4+ CD25+ CD44high cells and CD4+ CD25+ CD44low cells in LNs and the spleen as defined in A. Background BrdU staining levels were obtained from untreated mice (B). Representative results are shown and values indicate the mean ± SD of BrdU+ cells from data from two independent experiments (seven mice). The percentage of CD25+ CD4+ T cells was not statistically different in mice receiving osmotic pump with BrdU, mice receiving osmotic pump with PBS, and unmanipulated mice. In A, CD25+ CD4+ T cells represented 8.2% of CD4+ cells.
Mentions: To evaluate the recirculation properties, lifespan, turnover rate, and CD25 marker expression stability of the natural suppressor Treg, we transferred Treg purified from normal mice, having a diversified T cell repertoire, into unmanipulated nonlymphopenic normal Thy-1 congenic mice. We focused this study on the transfer of the CD62Lhigh Treg subset because we and others have previously demonstrated the high suppressive activity of this population in vivo (7, 32) and also because the CD4+ CD25+ CD62Lhigh cell population should contain low, if any, contamination with activated conventional CD4+ T lymphocytes, which display a CD4+ CD25+ CD62Llow phenotype (33). Experiments described below and shown in Figs. 1, 2, and 3 were all performed in the BALB/c genetic background. For all of these experiments, similar findings were observed in the C57BL/6 genetic background (unpublished data).

Bottom Line: In the steady state, some Treg remain quiescent and have a long lifespan, in the order of months, whereas the other Treg are dividing extensively and express multiple activation markers.After adoptive transfer, tissue-specific Treg rapidly divide and expand preferentially in lymph nodes draining their target self-antigens.These results reveal the existence of a cycling Treg subset composed of autoreactive Treg that are continuously activated by tissue self-antigens.

View Article: PubMed Central - PubMed

Affiliation: CNRS UMR 7087, Batiment CERVI, Hôpital de la Pitié-Salpêtrière, 83 Boulevard de l'Hôpital, 75013 Paris, France.

ABSTRACT
Despite a growing interest in CD4+ CD25+ regulatory T cells (Treg) that play a major role in self-tolerance and immunoregulation, fundamental parameters of the biology and homeostasis of these cells are poorly known. Here, we show that this population is composed of two Treg subsets that have distinct phenotypes and homeostasis in normal unmanipulated mice. In the steady state, some Treg remain quiescent and have a long lifespan, in the order of months, whereas the other Treg are dividing extensively and express multiple activation markers. After adoptive transfer, tissue-specific Treg rapidly divide and expand preferentially in lymph nodes draining their target self-antigens. These results reveal the existence of a cycling Treg subset composed of autoreactive Treg that are continuously activated by tissue self-antigens.

Show MeSH
Related in: MedlinePlus