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Massive thymic deletion results in systemic autoimmunity through elimination of CD4+ CD25+ T regulatory cells.

Shih FF, Mandik-Nayak L, Wipke BT, Allen PM - J. Exp. Med. (2004)

Bottom Line: Extensive thymic deletion resulted in lymphopenia and elimination of CD4+ CD25+ regulatory T cells (Tregs), but spared some CD4+ T cells expressing endogenous TCR, which oligoclonally expanded in the periphery.Thus, our studies demonstrated that central tolerance can paradoxically result in systemic autoimmunity through differential susceptibility of Tregs and autoreactive T cells to thymic deletion.Therefore, too little or too much negative selection to a self-antigen can result in systemic autoimmunity and disease.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.

ABSTRACT
Incomplete deletion of KRN T cells that recognize the ubiquitously expressed self-antigen glucose-6-phosphate-isomerase (GPI) initiates an anti-GPI autoimmune cascade in K/BxN mice resulting in a humorally mediated arthritis. Transgenic (Tg) expression of a KRN T cell receptor (TCR) agonist under the major histocompatibility complex class II promoter resulted in thymic deletion with loss of anti-GPI T and B cell responses and attenuated arthritis course. However, double Tg mice succumbed to systemic autoimmunity with multiorgan inflammation and autoantibody production. Extensive thymic deletion resulted in lymphopenia and elimination of CD4+ CD25+ regulatory T cells (Tregs), but spared some CD4+ T cells expressing endogenous TCR, which oligoclonally expanded in the periphery. Disease was transferred by these T cells and prevented by cotransfer of CD4+ CD25+ Tregs. Moreover, we extended our findings to another TCR system (anti-hen egg lysozyme [HEL] TCR/HEL mice) where similarly extensive thymic deletion also resulted in disease. Thus, our studies demonstrated that central tolerance can paradoxically result in systemic autoimmunity through differential susceptibility of Tregs and autoreactive T cells to thymic deletion. Therefore, too little or too much negative selection to a self-antigen can result in systemic autoimmunity and disease.

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Deletion of Vβ6hi CD4+ T cells in KRN/G7mTg7k/g7 mice. (A) CD4/CD8 profile of thymocytes and LN cells from KRNk, KRNk/g7, and KRN/G7mTg7k/g7 mice. Cell numbers are displayed above each plot. Numbers in each panel indicate percent of cells. Average thymocyte numbers were 190 ± 56 × 106, 72 ± 34 × 106, and 1.9 ± 0.8 × 106, and average LN cell numbers were 16 ± 7.8 × 106, 23 ± 13 × 106, and 0.9 ± 0.8 × 106 in KRNk, KRNk/g7, and KRN/G7mTg7k/g7 mice, respectively (n = 4). (B) Splenocytes from four KRNk/g7 (□) and four KRN/G7mTg7k/g7 (▪) mice were analyzed by flow cytometry for TCR Vβ gene expression. Each data point represents mean percent of total CD4+ T cells with error bar indicating ± SD. (C) CD4+ splenocytes were gated and analyzed for activation markers CD44-FITC, CD62L-PE, and CD25-PE. Data are representative of three independent experiments.
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fig4: Deletion of Vβ6hi CD4+ T cells in KRN/G7mTg7k/g7 mice. (A) CD4/CD8 profile of thymocytes and LN cells from KRNk, KRNk/g7, and KRN/G7mTg7k/g7 mice. Cell numbers are displayed above each plot. Numbers in each panel indicate percent of cells. Average thymocyte numbers were 190 ± 56 × 106, 72 ± 34 × 106, and 1.9 ± 0.8 × 106, and average LN cell numbers were 16 ± 7.8 × 106, 23 ± 13 × 106, and 0.9 ± 0.8 × 106 in KRNk, KRNk/g7, and KRN/G7mTg7k/g7 mice, respectively (n = 4). (B) Splenocytes from four KRNk/g7 (□) and four KRN/G7mTg7k/g7 (▪) mice were analyzed by flow cytometry for TCR Vβ gene expression. Each data point represents mean percent of total CD4+ T cells with error bar indicating ± SD. (C) CD4+ splenocytes were gated and analyzed for activation markers CD44-FITC, CD62L-PE, and CD25-PE. Data are representative of three independent experiments.

Mentions: Consistent with negative selection, there was graded reduction of thymocyte numbers in KRNk/g7 and KRN/G7mTg7k/g7 mice relative to KRNk mice (Fig. 4 A). Deletion of KRN T cells by endogenous GPI in KRNk/g7 mice was relatively inefficient as the thymocyte numbers were reduced only threefold with preservation of the CD4/CD8 profile. In contrast, thymocyte deletion in KRN/G7mTg7k/g7 mice was much more effective with a 100-fold reduction in total cellularity. Analysis of the CD4/CD8 compartments showed that the loss was primarily in the double positive thymocytes with preservation of CD4+ SP thymocytes compared with the CD8+ SP thymocytes.


Massive thymic deletion results in systemic autoimmunity through elimination of CD4+ CD25+ T regulatory cells.

Shih FF, Mandik-Nayak L, Wipke BT, Allen PM - J. Exp. Med. (2004)

Deletion of Vβ6hi CD4+ T cells in KRN/G7mTg7k/g7 mice. (A) CD4/CD8 profile of thymocytes and LN cells from KRNk, KRNk/g7, and KRN/G7mTg7k/g7 mice. Cell numbers are displayed above each plot. Numbers in each panel indicate percent of cells. Average thymocyte numbers were 190 ± 56 × 106, 72 ± 34 × 106, and 1.9 ± 0.8 × 106, and average LN cell numbers were 16 ± 7.8 × 106, 23 ± 13 × 106, and 0.9 ± 0.8 × 106 in KRNk, KRNk/g7, and KRN/G7mTg7k/g7 mice, respectively (n = 4). (B) Splenocytes from four KRNk/g7 (□) and four KRN/G7mTg7k/g7 (▪) mice were analyzed by flow cytometry for TCR Vβ gene expression. Each data point represents mean percent of total CD4+ T cells with error bar indicating ± SD. (C) CD4+ splenocytes were gated and analyzed for activation markers CD44-FITC, CD62L-PE, and CD25-PE. Data are representative of three independent experiments.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2211803&req=5

fig4: Deletion of Vβ6hi CD4+ T cells in KRN/G7mTg7k/g7 mice. (A) CD4/CD8 profile of thymocytes and LN cells from KRNk, KRNk/g7, and KRN/G7mTg7k/g7 mice. Cell numbers are displayed above each plot. Numbers in each panel indicate percent of cells. Average thymocyte numbers were 190 ± 56 × 106, 72 ± 34 × 106, and 1.9 ± 0.8 × 106, and average LN cell numbers were 16 ± 7.8 × 106, 23 ± 13 × 106, and 0.9 ± 0.8 × 106 in KRNk, KRNk/g7, and KRN/G7mTg7k/g7 mice, respectively (n = 4). (B) Splenocytes from four KRNk/g7 (□) and four KRN/G7mTg7k/g7 (▪) mice were analyzed by flow cytometry for TCR Vβ gene expression. Each data point represents mean percent of total CD4+ T cells with error bar indicating ± SD. (C) CD4+ splenocytes were gated and analyzed for activation markers CD44-FITC, CD62L-PE, and CD25-PE. Data are representative of three independent experiments.
Mentions: Consistent with negative selection, there was graded reduction of thymocyte numbers in KRNk/g7 and KRN/G7mTg7k/g7 mice relative to KRNk mice (Fig. 4 A). Deletion of KRN T cells by endogenous GPI in KRNk/g7 mice was relatively inefficient as the thymocyte numbers were reduced only threefold with preservation of the CD4/CD8 profile. In contrast, thymocyte deletion in KRN/G7mTg7k/g7 mice was much more effective with a 100-fold reduction in total cellularity. Analysis of the CD4/CD8 compartments showed that the loss was primarily in the double positive thymocytes with preservation of CD4+ SP thymocytes compared with the CD8+ SP thymocytes.

Bottom Line: Extensive thymic deletion resulted in lymphopenia and elimination of CD4+ CD25+ regulatory T cells (Tregs), but spared some CD4+ T cells expressing endogenous TCR, which oligoclonally expanded in the periphery.Thus, our studies demonstrated that central tolerance can paradoxically result in systemic autoimmunity through differential susceptibility of Tregs and autoreactive T cells to thymic deletion.Therefore, too little or too much negative selection to a self-antigen can result in systemic autoimmunity and disease.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110, USA.

ABSTRACT
Incomplete deletion of KRN T cells that recognize the ubiquitously expressed self-antigen glucose-6-phosphate-isomerase (GPI) initiates an anti-GPI autoimmune cascade in K/BxN mice resulting in a humorally mediated arthritis. Transgenic (Tg) expression of a KRN T cell receptor (TCR) agonist under the major histocompatibility complex class II promoter resulted in thymic deletion with loss of anti-GPI T and B cell responses and attenuated arthritis course. However, double Tg mice succumbed to systemic autoimmunity with multiorgan inflammation and autoantibody production. Extensive thymic deletion resulted in lymphopenia and elimination of CD4+ CD25+ regulatory T cells (Tregs), but spared some CD4+ T cells expressing endogenous TCR, which oligoclonally expanded in the periphery. Disease was transferred by these T cells and prevented by cotransfer of CD4+ CD25+ Tregs. Moreover, we extended our findings to another TCR system (anti-hen egg lysozyme [HEL] TCR/HEL mice) where similarly extensive thymic deletion also resulted in disease. Thus, our studies demonstrated that central tolerance can paradoxically result in systemic autoimmunity through differential susceptibility of Tregs and autoreactive T cells to thymic deletion. Therefore, too little or too much negative selection to a self-antigen can result in systemic autoimmunity and disease.

Show MeSH
Related in: MedlinePlus