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Perinatal blockade of b7-1 and b7-2 inhibits clonal deletion of highly pathogenic autoreactive T cells.

Gao JX, Zhang H, Bai XF, Wen J, Zheng X, Liu J, Zheng P, Liu Y - J. Exp. Med. (2002)

Bottom Line: A number of in vitro studies have suggested that costimulatory molecules B7-1 and B7-2 and their receptor CD28 can promote clonal deletion, and limited in vivo studies have indicated that CD28 is involved in the clonal deletion of some T cells.Here we report that the perinatal blockade of B7-1 and B7-2 substantially inhibits the clonal deletion of T cells in the thymus and leads to an accumulation of T cells capable of inducing fatal multiorgan inflammation.These results reveal a critical role for costimulatory molecules B7-1 and B7-2 in deleting pathogenic autoreactive T cells in the thymus.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology and Comprehensive Cancer Center, Division of Cancer Immunology, Ohio State University Medical Center, Columbus, OH 43210, USA.

ABSTRACT
A number of in vitro studies have suggested that costimulatory molecules B7-1 and B7-2 and their receptor CD28 can promote clonal deletion, and limited in vivo studies have indicated that CD28 is involved in the clonal deletion of some T cells. However, the significance of B7-mediated clonal deletion in preventing autoimmune diseases has not been studied systematically. Here we report that the perinatal blockade of B7-1 and B7-2 substantially inhibits the clonal deletion of T cells in the thymus and leads to an accumulation of T cells capable of inducing fatal multiorgan inflammation. These results reveal a critical role for costimulatory molecules B7-1 and B7-2 in deleting pathogenic autoreactive T cells in the thymus. The critical role of B7-1 and B7-2 in T cell clonal deletion may explain, at least in part, the paradoxical increase of autoimmune disease in mice deficient for this family of costimulatory molecules, such as cytotoxic T lymphocyte associated molecule 4, CD28, and B7-2. The strong pathogenicity of the self-reactive T cells supports a central hypothesis in immunology, which is that clonal deletion plays an important role in preventing autoimmune diseases.

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Anti-B7 blockade in the perinatal period (from E16 to day 10 after birth) significantly reduced the efficacy of T cell clonal deletion, analyzed on day 15 after birth. (a) Anti-B7 mAb increased the total number of thymocytes in transgenic mice expressing both the T cell receptor and its specific antigen. Data shown are summarized from three independent experiments. Each point represents one double transgenic mouse. (b) Thymocyte composition in TCR single transgenic (P1CTL+/P1A−) or TCR P1A double transgenic (P1ACTL+/P1A+) mice. Transgenic thymocytes were analyzed by three-color flow cytometry using anti-Vα8, anti-CD4, and anti-CD8 mAbs. The number of thymocytes is given at the bottom of each panel, and the percentage of the Vα8+ cells is provided in the parentheses. Data shown are profiles of gated Vα8+ T cells and are representative of three independent experiments. (c) The subset distribution of gated Vα8− T cells from either anti-B7 or control Ig-treated double transgenic mice. The percentage of the gated population is presented at the bottom of each panel.
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fig1: Anti-B7 blockade in the perinatal period (from E16 to day 10 after birth) significantly reduced the efficacy of T cell clonal deletion, analyzed on day 15 after birth. (a) Anti-B7 mAb increased the total number of thymocytes in transgenic mice expressing both the T cell receptor and its specific antigen. Data shown are summarized from three independent experiments. Each point represents one double transgenic mouse. (b) Thymocyte composition in TCR single transgenic (P1CTL+/P1A−) or TCR P1A double transgenic (P1ACTL+/P1A+) mice. Transgenic thymocytes were analyzed by three-color flow cytometry using anti-Vα8, anti-CD4, and anti-CD8 mAbs. The number of thymocytes is given at the bottom of each panel, and the percentage of the Vα8+ cells is provided in the parentheses. Data shown are profiles of gated Vα8+ T cells and are representative of three independent experiments. (c) The subset distribution of gated Vα8− T cells from either anti-B7 or control Ig-treated double transgenic mice. The percentage of the gated population is presented at the bottom of each panel.

Mentions: We have recently produced a transgenic mouse line that overexpresses tumor antigen P1A in the thymus and in the spleen, and another transgenic line that expresses H-2Ld–restricted, P1A-specific TCR (P1CTL) (19). We reported that thymic expression of P1A led to the clonal deletion of P1A-specific T cells in the P1CTL+/P1A+ mice (19). To test the effect of B7 blockade in T cell development, we bred P1A transgenic mice with the TCR transgenic mice and injected anti-B7 or control antibodies from E16 to day 10 after birth. The effects of anti-B7 mAbs on the littermates that expressed either P1CTL TCR alone or both TCR and the P1A in the thymus were analyzed by flow cytometry on day 15 after birth. As shown in Fig. 1 a, perinatal treatment with anti-B7 mAbs substantially increased the number of T cells in the double transgenic mice. Within the control IgG-treated group, expression of P1A led to the clonal deletion of P1CTL, as indicated by a reduction in the total number of thymocytes and a specific reduction of the number of CD4+CD8+ thymocytes (Fig. 1 b). Both effects were reversed by perinatal treatment with anti-B7 mAbs. These results demonstrated that anti-B7 mAbs prevented the clonal deletion of the P1A-specific T cells.


Perinatal blockade of b7-1 and b7-2 inhibits clonal deletion of highly pathogenic autoreactive T cells.

Gao JX, Zhang H, Bai XF, Wen J, Zheng X, Liu J, Zheng P, Liu Y - J. Exp. Med. (2002)

Anti-B7 blockade in the perinatal period (from E16 to day 10 after birth) significantly reduced the efficacy of T cell clonal deletion, analyzed on day 15 after birth. (a) Anti-B7 mAb increased the total number of thymocytes in transgenic mice expressing both the T cell receptor and its specific antigen. Data shown are summarized from three independent experiments. Each point represents one double transgenic mouse. (b) Thymocyte composition in TCR single transgenic (P1CTL+/P1A−) or TCR P1A double transgenic (P1ACTL+/P1A+) mice. Transgenic thymocytes were analyzed by three-color flow cytometry using anti-Vα8, anti-CD4, and anti-CD8 mAbs. The number of thymocytes is given at the bottom of each panel, and the percentage of the Vα8+ cells is provided in the parentheses. Data shown are profiles of gated Vα8+ T cells and are representative of three independent experiments. (c) The subset distribution of gated Vα8− T cells from either anti-B7 or control Ig-treated double transgenic mice. The percentage of the gated population is presented at the bottom of each panel.
© Copyright Policy
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2193695&req=5

fig1: Anti-B7 blockade in the perinatal period (from E16 to day 10 after birth) significantly reduced the efficacy of T cell clonal deletion, analyzed on day 15 after birth. (a) Anti-B7 mAb increased the total number of thymocytes in transgenic mice expressing both the T cell receptor and its specific antigen. Data shown are summarized from three independent experiments. Each point represents one double transgenic mouse. (b) Thymocyte composition in TCR single transgenic (P1CTL+/P1A−) or TCR P1A double transgenic (P1ACTL+/P1A+) mice. Transgenic thymocytes were analyzed by three-color flow cytometry using anti-Vα8, anti-CD4, and anti-CD8 mAbs. The number of thymocytes is given at the bottom of each panel, and the percentage of the Vα8+ cells is provided in the parentheses. Data shown are profiles of gated Vα8+ T cells and are representative of three independent experiments. (c) The subset distribution of gated Vα8− T cells from either anti-B7 or control Ig-treated double transgenic mice. The percentage of the gated population is presented at the bottom of each panel.
Mentions: We have recently produced a transgenic mouse line that overexpresses tumor antigen P1A in the thymus and in the spleen, and another transgenic line that expresses H-2Ld–restricted, P1A-specific TCR (P1CTL) (19). We reported that thymic expression of P1A led to the clonal deletion of P1A-specific T cells in the P1CTL+/P1A+ mice (19). To test the effect of B7 blockade in T cell development, we bred P1A transgenic mice with the TCR transgenic mice and injected anti-B7 or control antibodies from E16 to day 10 after birth. The effects of anti-B7 mAbs on the littermates that expressed either P1CTL TCR alone or both TCR and the P1A in the thymus were analyzed by flow cytometry on day 15 after birth. As shown in Fig. 1 a, perinatal treatment with anti-B7 mAbs substantially increased the number of T cells in the double transgenic mice. Within the control IgG-treated group, expression of P1A led to the clonal deletion of P1CTL, as indicated by a reduction in the total number of thymocytes and a specific reduction of the number of CD4+CD8+ thymocytes (Fig. 1 b). Both effects were reversed by perinatal treatment with anti-B7 mAbs. These results demonstrated that anti-B7 mAbs prevented the clonal deletion of the P1A-specific T cells.

Bottom Line: A number of in vitro studies have suggested that costimulatory molecules B7-1 and B7-2 and their receptor CD28 can promote clonal deletion, and limited in vivo studies have indicated that CD28 is involved in the clonal deletion of some T cells.Here we report that the perinatal blockade of B7-1 and B7-2 substantially inhibits the clonal deletion of T cells in the thymus and leads to an accumulation of T cells capable of inducing fatal multiorgan inflammation.These results reveal a critical role for costimulatory molecules B7-1 and B7-2 in deleting pathogenic autoreactive T cells in the thymus.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology and Comprehensive Cancer Center, Division of Cancer Immunology, Ohio State University Medical Center, Columbus, OH 43210, USA.

ABSTRACT
A number of in vitro studies have suggested that costimulatory molecules B7-1 and B7-2 and their receptor CD28 can promote clonal deletion, and limited in vivo studies have indicated that CD28 is involved in the clonal deletion of some T cells. However, the significance of B7-mediated clonal deletion in preventing autoimmune diseases has not been studied systematically. Here we report that the perinatal blockade of B7-1 and B7-2 substantially inhibits the clonal deletion of T cells in the thymus and leads to an accumulation of T cells capable of inducing fatal multiorgan inflammation. These results reveal a critical role for costimulatory molecules B7-1 and B7-2 in deleting pathogenic autoreactive T cells in the thymus. The critical role of B7-1 and B7-2 in T cell clonal deletion may explain, at least in part, the paradoxical increase of autoimmune disease in mice deficient for this family of costimulatory molecules, such as cytotoxic T lymphocyte associated molecule 4, CD28, and B7-2. The strong pathogenicity of the self-reactive T cells supports a central hypothesis in immunology, which is that clonal deletion plays an important role in preventing autoimmune diseases.

Show MeSH
Related in: MedlinePlus