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Normal regulatory alpha/beta T cells effectively eliminate abnormally activated T cells lacking the interleukin 2 receptor beta in vivo.

Suzuki H, Zhou YW, Kato M, Mak TW, Nakashima I - J. Exp. Med. (1999)

Bottom Line: Although interleukin 2 (IL-2) has been thought to be the most important cytokine for T cell growth, animals lacking IL-2 or a component of its receptor molecules have more expanded T cells with activated memory phenotype, indicating an indispensable role for the IL-2/IL-2 receptor system in regulating the size and activity of the T cell population.This regulation and/or elimination was dependent on T cells bearing alpha/beta type T cell receptor, especially on CD8(+) T cells and independent of the Fas-Fas ligand (FasL) system.These results indicate a novel function of IL-2Rbeta that is necessary for the induction of regulatory T cells acting to eliminate activated T cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology, Nagoya University School of Medicine, Nagoya 466-8550, Japan. k46200a@nucc.cc.nagoya-u.ac.jp

ABSTRACT
Although interleukin 2 (IL-2) has been thought to be the most important cytokine for T cell growth, animals lacking IL-2 or a component of its receptor molecules have more expanded T cells with activated memory phenotype, indicating an indispensable role for the IL-2/IL-2 receptor system in regulating the size and activity of the T cell population. In this study, we investigated the possible mechanism of abnormal expansion of activated T cells in IL-2 receptor beta chain (IL-2Rbeta)(-/-) mice using the systems of bone marrow transplantation and T cell transfer. Here, we show that IL-2Rbeta(2/-) T cells in mice reconstituted with a mixture of IL-2Rbeta(2/-) and IL-2Rbeta(1/+) bone marrow cells did not develop into an abnormally activated stage, and that already activated IL-2Rbeta(2/-) T cells were effectively eliminated by IL-2Rbeta(1/+) T cells when both cells were cotransferred to T cell-deficient host mice. This regulation and/or elimination was dependent on T cells bearing alpha/beta type T cell receptor, especially on CD8(+) T cells and independent of the Fas-Fas ligand (FasL) system. IL-2Rbeta(1/+) T cells that eliminated activated IL-2Rbeta(2/-) T cells expressed FasL, perforin, granzyme B, and tumor necrosis factor alpha/beta. These results indicate a novel function of IL-2Rbeta that is necessary for the induction of regulatory T cells acting to eliminate activated T cells.

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No abnormal T cell activation in chimeric mice reconstituted with a mixture of IL-2Rβ2/− and IL-2Rβ1/+ bone marrow (BM) cells. Bone marrow of B6.RAG-2−/− mice was reconstituted with IL-2Rβ1/+ alone (top row), a mixture of IL-2Rβ2/− and IL-2Rβ1/+ (second row), or IL-2Rβ2/− alone (third row), and their lymph node cells were analyzed for the expression of CD69 and CD62L. Lymph node cells obtained from the indicated mice 6 wk after bone marrow transplantation were stained with a mixture of FITC-conjugated anti-CD69, PE-conjugated anti–Thy-1.2, and biotin-conjugated anti-CD45.1 antibodies, or with a mixture of FITC-conjugated anti–Thy-1.2, PE-conjugated anti-CD62L, and biotin-conjugated anti-CD45.1 antibodies, then secondarily stained with streptavidin-conjugated RED670. Bold lines represent the expression of CD69 or CD62L in cells gated to Thy-1.2+CD45.1+ population (IL-2Rβ2/−–derived T cells). Thin lines represent the expression in cells gated to Thy-1.2+CD45.1− population (IL-2Rβ1/+–derived T cells). The bottom row shows the expression of CD69 and CD62L in T cells from a 6-wk-old IL-2Rβ2/− mouse.
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Figure 1: No abnormal T cell activation in chimeric mice reconstituted with a mixture of IL-2Rβ2/− and IL-2Rβ1/+ bone marrow (BM) cells. Bone marrow of B6.RAG-2−/− mice was reconstituted with IL-2Rβ1/+ alone (top row), a mixture of IL-2Rβ2/− and IL-2Rβ1/+ (second row), or IL-2Rβ2/− alone (third row), and their lymph node cells were analyzed for the expression of CD69 and CD62L. Lymph node cells obtained from the indicated mice 6 wk after bone marrow transplantation were stained with a mixture of FITC-conjugated anti-CD69, PE-conjugated anti–Thy-1.2, and biotin-conjugated anti-CD45.1 antibodies, or with a mixture of FITC-conjugated anti–Thy-1.2, PE-conjugated anti-CD62L, and biotin-conjugated anti-CD45.1 antibodies, then secondarily stained with streptavidin-conjugated RED670. Bold lines represent the expression of CD69 or CD62L in cells gated to Thy-1.2+CD45.1+ population (IL-2Rβ2/−–derived T cells). Thin lines represent the expression in cells gated to Thy-1.2+CD45.1− population (IL-2Rβ1/+–derived T cells). The bottom row shows the expression of CD69 and CD62L in T cells from a 6-wk-old IL-2Rβ2/− mouse.

Mentions: To investigate the mechanism of abnormal development of multiple hematopoietic cells in IL-2Rβ2/− mice, we first examined bone marrow chimeric mice reconstituted with IL-2Rβ2/− bone marrow cells. When lymphocyte-deficient RAG-2−/− mice were reconstituted with IL-2Rβ2/− bone marrow cells, T cells arising from the transferred bone marrow cells later than 6 wk showed a markedly activated memory phenotype of CD69+CD62Llo (Fig. 1, IL-2Rβ2/− BM chimera), CD44hi, and CD45RBlo (data not shown), all of which were characteristic features of T cells in IL-2Rβ2/− mice (Fig. 1, IL-2Rβ2/− [9]). These mice also showed phenotypes of decreased B220+ cells in lymphatic organs, increased Gr-1+ cells in bone marrow, and anemia (data not shown), all of which were observed in IL-2Rβ2/− mice 9, indicating that most phenotypes caused by IL-2Rβ deficiency were restored by bone marrow reconstitution. However, when RAG-2−/− mice were reconstituted with a mixture of IL-2Rβ1/+ and IL-2Rβ2/− bone marrow cells, T cells arising from IL-2Rβ2/− bone marrow cells, which were distinguished from IL-2Rβ1/+–derived cells by CD45 allotype-specific antibody and were shown to exist with a number similar to that in simple IL-2Rβ2/− bone marrow chimera, showed no sign of activation (Fig. 1, IL-2Rβ1/+ + IL-2Rβ2/− BM chimera). B cells, granulocytes, and erythrocytes were also normal in these mice (data not shown), and inflammatory bowel disease was never observed. This result indicates that IL-2Rβ2/− T cells do not develop into an abnormally activated phenotype when they exist together with normal IL-2Rβ1/+ cells, which may have the activity to regulate the abnormal activation of IL-2Rβ2/− T cells.


Normal regulatory alpha/beta T cells effectively eliminate abnormally activated T cells lacking the interleukin 2 receptor beta in vivo.

Suzuki H, Zhou YW, Kato M, Mak TW, Nakashima I - J. Exp. Med. (1999)

No abnormal T cell activation in chimeric mice reconstituted with a mixture of IL-2Rβ2/− and IL-2Rβ1/+ bone marrow (BM) cells. Bone marrow of B6.RAG-2−/− mice was reconstituted with IL-2Rβ1/+ alone (top row), a mixture of IL-2Rβ2/− and IL-2Rβ1/+ (second row), or IL-2Rβ2/− alone (third row), and their lymph node cells were analyzed for the expression of CD69 and CD62L. Lymph node cells obtained from the indicated mice 6 wk after bone marrow transplantation were stained with a mixture of FITC-conjugated anti-CD69, PE-conjugated anti–Thy-1.2, and biotin-conjugated anti-CD45.1 antibodies, or with a mixture of FITC-conjugated anti–Thy-1.2, PE-conjugated anti-CD62L, and biotin-conjugated anti-CD45.1 antibodies, then secondarily stained with streptavidin-conjugated RED670. Bold lines represent the expression of CD69 or CD62L in cells gated to Thy-1.2+CD45.1+ population (IL-2Rβ2/−–derived T cells). Thin lines represent the expression in cells gated to Thy-1.2+CD45.1− population (IL-2Rβ1/+–derived T cells). The bottom row shows the expression of CD69 and CD62L in T cells from a 6-wk-old IL-2Rβ2/− mouse.
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Related In: Results  -  Collection

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Figure 1: No abnormal T cell activation in chimeric mice reconstituted with a mixture of IL-2Rβ2/− and IL-2Rβ1/+ bone marrow (BM) cells. Bone marrow of B6.RAG-2−/− mice was reconstituted with IL-2Rβ1/+ alone (top row), a mixture of IL-2Rβ2/− and IL-2Rβ1/+ (second row), or IL-2Rβ2/− alone (third row), and their lymph node cells were analyzed for the expression of CD69 and CD62L. Lymph node cells obtained from the indicated mice 6 wk after bone marrow transplantation were stained with a mixture of FITC-conjugated anti-CD69, PE-conjugated anti–Thy-1.2, and biotin-conjugated anti-CD45.1 antibodies, or with a mixture of FITC-conjugated anti–Thy-1.2, PE-conjugated anti-CD62L, and biotin-conjugated anti-CD45.1 antibodies, then secondarily stained with streptavidin-conjugated RED670. Bold lines represent the expression of CD69 or CD62L in cells gated to Thy-1.2+CD45.1+ population (IL-2Rβ2/−–derived T cells). Thin lines represent the expression in cells gated to Thy-1.2+CD45.1− population (IL-2Rβ1/+–derived T cells). The bottom row shows the expression of CD69 and CD62L in T cells from a 6-wk-old IL-2Rβ2/− mouse.
Mentions: To investigate the mechanism of abnormal development of multiple hematopoietic cells in IL-2Rβ2/− mice, we first examined bone marrow chimeric mice reconstituted with IL-2Rβ2/− bone marrow cells. When lymphocyte-deficient RAG-2−/− mice were reconstituted with IL-2Rβ2/− bone marrow cells, T cells arising from the transferred bone marrow cells later than 6 wk showed a markedly activated memory phenotype of CD69+CD62Llo (Fig. 1, IL-2Rβ2/− BM chimera), CD44hi, and CD45RBlo (data not shown), all of which were characteristic features of T cells in IL-2Rβ2/− mice (Fig. 1, IL-2Rβ2/− [9]). These mice also showed phenotypes of decreased B220+ cells in lymphatic organs, increased Gr-1+ cells in bone marrow, and anemia (data not shown), all of which were observed in IL-2Rβ2/− mice 9, indicating that most phenotypes caused by IL-2Rβ deficiency were restored by bone marrow reconstitution. However, when RAG-2−/− mice were reconstituted with a mixture of IL-2Rβ1/+ and IL-2Rβ2/− bone marrow cells, T cells arising from IL-2Rβ2/− bone marrow cells, which were distinguished from IL-2Rβ1/+–derived cells by CD45 allotype-specific antibody and were shown to exist with a number similar to that in simple IL-2Rβ2/− bone marrow chimera, showed no sign of activation (Fig. 1, IL-2Rβ1/+ + IL-2Rβ2/− BM chimera). B cells, granulocytes, and erythrocytes were also normal in these mice (data not shown), and inflammatory bowel disease was never observed. This result indicates that IL-2Rβ2/− T cells do not develop into an abnormally activated phenotype when they exist together with normal IL-2Rβ1/+ cells, which may have the activity to regulate the abnormal activation of IL-2Rβ2/− T cells.

Bottom Line: Although interleukin 2 (IL-2) has been thought to be the most important cytokine for T cell growth, animals lacking IL-2 or a component of its receptor molecules have more expanded T cells with activated memory phenotype, indicating an indispensable role for the IL-2/IL-2 receptor system in regulating the size and activity of the T cell population.This regulation and/or elimination was dependent on T cells bearing alpha/beta type T cell receptor, especially on CD8(+) T cells and independent of the Fas-Fas ligand (FasL) system.These results indicate a novel function of IL-2Rbeta that is necessary for the induction of regulatory T cells acting to eliminate activated T cells.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology, Nagoya University School of Medicine, Nagoya 466-8550, Japan. k46200a@nucc.cc.nagoya-u.ac.jp

ABSTRACT
Although interleukin 2 (IL-2) has been thought to be the most important cytokine for T cell growth, animals lacking IL-2 or a component of its receptor molecules have more expanded T cells with activated memory phenotype, indicating an indispensable role for the IL-2/IL-2 receptor system in regulating the size and activity of the T cell population. In this study, we investigated the possible mechanism of abnormal expansion of activated T cells in IL-2 receptor beta chain (IL-2Rbeta)(-/-) mice using the systems of bone marrow transplantation and T cell transfer. Here, we show that IL-2Rbeta(2/-) T cells in mice reconstituted with a mixture of IL-2Rbeta(2/-) and IL-2Rbeta(1/+) bone marrow cells did not develop into an abnormally activated stage, and that already activated IL-2Rbeta(2/-) T cells were effectively eliminated by IL-2Rbeta(1/+) T cells when both cells were cotransferred to T cell-deficient host mice. This regulation and/or elimination was dependent on T cells bearing alpha/beta type T cell receptor, especially on CD8(+) T cells and independent of the Fas-Fas ligand (FasL) system. IL-2Rbeta(1/+) T cells that eliminated activated IL-2Rbeta(2/-) T cells expressed FasL, perforin, granzyme B, and tumor necrosis factor alpha/beta. These results indicate a novel function of IL-2Rbeta that is necessary for the induction of regulatory T cells acting to eliminate activated T cells.

Show MeSH
Related in: MedlinePlus