Limits...
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.

Show MeSH

Related in: MedlinePlus

Autoimmune inflammatory response in mice that received anti-B7 mAbs during the perinatal period. 2 mo after the antibody treatment, the mice were killed and the internal organs were fixed with 10% formalin and examined by H&E staining. (a) Scores of histological lesions in either control (○) or anti–B7-treated mice (•). The scores of lung and kidney lesions were presented. The data shown are summarized from three independent experiments. (b) Phenotypic and functional characterization of the spleen T cells. Spleen cells were analyzed for the cell surface expression of CD69 and CD62L and intracellular expression of IFN-γ. The subsets of T cells were marked by a combination of FITC-conjugated anti-CD4 and Cychrome–conjugated anti-CD8 mAbs. Data from gated CD4 T cells are presented, although similar results were obtained among the gated CD8 T cells. No alteration in the number of IL-2–, IL-4–, and IL-10–producing cells was observed. Data shown are representative of three independent experiments.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2193695&req=5

fig8: Autoimmune inflammatory response in mice that received anti-B7 mAbs during the perinatal period. 2 mo after the antibody treatment, the mice were killed and the internal organs were fixed with 10% formalin and examined by H&E staining. (a) Scores of histological lesions in either control (○) or anti–B7-treated mice (•). The scores of lung and kidney lesions were presented. The data shown are summarized from three independent experiments. (b) Phenotypic and functional characterization of the spleen T cells. Spleen cells were analyzed for the cell surface expression of CD69 and CD62L and intracellular expression of IFN-γ. The subsets of T cells were marked by a combination of FITC-conjugated anti-CD4 and Cychrome–conjugated anti-CD8 mAbs. Data from gated CD4 T cells are presented, although similar results were obtained among the gated CD8 T cells. No alteration in the number of IL-2–, IL-4–, and IL-10–producing cells was observed. Data shown are representative of three independent experiments.

Mentions: To test if the mice that received anti-B7 mAbs during the perinatal period developed autoimmune diseases, the mice were left untreated after the perinatal period and killed for histological examination 1, 2, and 5 mo after antibody treatment. In comparison to control IgG-treated mice, the anti–B7-treated mice had increases in both the number and severity of pathological lesions in multiple organs as early as 1 mo after the antibody treatments (unpublished data). 2 mo after treatment, the inflammation exacerbated substantially. The pathological and immunological effects of perinatal treatment with anti-B7 mAbs are presented in Fig. 8 . As shown in Fig. 8 a, both male and female mice that received anti-B7 during the perinatal period had severe mononuclear cell infiltration in the lung. The majority of anti–B7-treated female mice had inflammation in the kidney, whereas the control female mice had little kidney inflammation. No inflammation in the kidney was observed in male mice regardless of the treatment during the perinatal period. Corresponding to increased pathological lesions, lymphoproliferation was observed in anti–B7-treated mice. Thus, in comparison with control IgG-treated mice, the T cell numbers in the lymph nodes increased by three- to fivefold (unpublished data). The number of activated T cells, as indicated by CD69hi and CD62Llo phenotypes, also increased significantly (Fig. 8 b). The percentage of IFN-γ–producing cells increased by threefold in anti–B7-treated mice (Fig. 8 b). By month 5, although the numbers of IFN-γ–producing cells remained higher, the pathological lesions were largely resolved in anti–B7-treated mice (unpublished data), perhaps due to immune regulation by the endogenous 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)

Autoimmune inflammatory response in mice that received anti-B7 mAbs during the perinatal period. 2 mo after the antibody treatment, the mice were killed and the internal organs were fixed with 10% formalin and examined by H&E staining. (a) Scores of histological lesions in either control (○) or anti–B7-treated mice (•). The scores of lung and kidney lesions were presented. The data shown are summarized from three independent experiments. (b) Phenotypic and functional characterization of the spleen T cells. Spleen cells were analyzed for the cell surface expression of CD69 and CD62L and intracellular expression of IFN-γ. The subsets of T cells were marked by a combination of FITC-conjugated anti-CD4 and Cychrome–conjugated anti-CD8 mAbs. Data from gated CD4 T cells are presented, although similar results were obtained among the gated CD8 T cells. No alteration in the number of IL-2–, IL-4–, and IL-10–producing cells was observed. Data shown are representative of three independent experiments.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2193695&req=5

fig8: Autoimmune inflammatory response in mice that received anti-B7 mAbs during the perinatal period. 2 mo after the antibody treatment, the mice were killed and the internal organs were fixed with 10% formalin and examined by H&E staining. (a) Scores of histological lesions in either control (○) or anti–B7-treated mice (•). The scores of lung and kidney lesions were presented. The data shown are summarized from three independent experiments. (b) Phenotypic and functional characterization of the spleen T cells. Spleen cells were analyzed for the cell surface expression of CD69 and CD62L and intracellular expression of IFN-γ. The subsets of T cells were marked by a combination of FITC-conjugated anti-CD4 and Cychrome–conjugated anti-CD8 mAbs. Data from gated CD4 T cells are presented, although similar results were obtained among the gated CD8 T cells. No alteration in the number of IL-2–, IL-4–, and IL-10–producing cells was observed. Data shown are representative of three independent experiments.
Mentions: To test if the mice that received anti-B7 mAbs during the perinatal period developed autoimmune diseases, the mice were left untreated after the perinatal period and killed for histological examination 1, 2, and 5 mo after antibody treatment. In comparison to control IgG-treated mice, the anti–B7-treated mice had increases in both the number and severity of pathological lesions in multiple organs as early as 1 mo after the antibody treatments (unpublished data). 2 mo after treatment, the inflammation exacerbated substantially. The pathological and immunological effects of perinatal treatment with anti-B7 mAbs are presented in Fig. 8 . As shown in Fig. 8 a, both male and female mice that received anti-B7 during the perinatal period had severe mononuclear cell infiltration in the lung. The majority of anti–B7-treated female mice had inflammation in the kidney, whereas the control female mice had little kidney inflammation. No inflammation in the kidney was observed in male mice regardless of the treatment during the perinatal period. Corresponding to increased pathological lesions, lymphoproliferation was observed in anti–B7-treated mice. Thus, in comparison with control IgG-treated mice, the T cell numbers in the lymph nodes increased by three- to fivefold (unpublished data). The number of activated T cells, as indicated by CD69hi and CD62Llo phenotypes, also increased significantly (Fig. 8 b). The percentage of IFN-γ–producing cells increased by threefold in anti–B7-treated mice (Fig. 8 b). By month 5, although the numbers of IFN-γ–producing cells remained higher, the pathological lesions were largely resolved in anti–B7-treated mice (unpublished data), perhaps due to immune regulation by the endogenous 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