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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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KRN/G7mTg7k/g7 mice exhibited reduced arthritis and anti-GPI antibodies. (A) Mean ankle thickness ± SD of 6 KRNk/g7 (⋄) and 10 KRN/G7mTg7k/g7 (•) mice. Data are representative of 20 KRNk/g7 and 16 KRN/G7mTg7k/g7 mice derived from 14 separate litters of mice collected over a 6-mo period. (B) Absorbance of anti-GPI ELISA of KRNk/g7 (⋄), KRN/G7mTg7k/g7 (•), G7mTg7k/g7 (▵), and double negative (DN; ○) mice (n = 15, 20, 23, and 12, respectively). Sera from 8-wk-old mice were diluted at 1:100 and serum anti-GPI was detected by ELISA. Each symbol represents an individual mouse. (C) T cell proliferation in response to GPI(281–293). 5 × 105 splenocytes from KRNk/g7 (▪), KRN/G7mTg7k/g7 (•), and transgene-negative (▵) mice were cultured with graded doses of GPI(281–293) peptide with 2 × 105 irradiated H-2k/g7 splenocytes in 96-well round-bottom plates for 72 h with 0.2 μCi [3H]thymidine in the last 18 h. Each point represents the mean of triplicate wells with error bars indicating SD. Data are representative of three independent experiments.
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fig2: KRN/G7mTg7k/g7 mice exhibited reduced arthritis and anti-GPI antibodies. (A) Mean ankle thickness ± SD of 6 KRNk/g7 (⋄) and 10 KRN/G7mTg7k/g7 (•) mice. Data are representative of 20 KRNk/g7 and 16 KRN/G7mTg7k/g7 mice derived from 14 separate litters of mice collected over a 6-mo period. (B) Absorbance of anti-GPI ELISA of KRNk/g7 (⋄), KRN/G7mTg7k/g7 (•), G7mTg7k/g7 (▵), and double negative (DN; ○) mice (n = 15, 20, 23, and 12, respectively). Sera from 8-wk-old mice were diluted at 1:100 and serum anti-GPI was detected by ELISA. Each symbol represents an individual mouse. (C) T cell proliferation in response to GPI(281–293). 5 × 105 splenocytes from KRNk/g7 (▪), KRN/G7mTg7k/g7 (•), and transgene-negative (▵) mice were cultured with graded doses of GPI(281–293) peptide with 2 × 105 irradiated H-2k/g7 splenocytes in 96-well round-bottom plates for 72 h with 0.2 μCi [3H]thymidine in the last 18 h. Each point represents the mean of triplicate wells with error bars indicating SD. Data are representative of three independent experiments.

Mentions: KRNk/g7 and KRN/G7mTg7k/g7 mice were followed for the onset and severity of arthritis starting at 4 wk of age. Arthritis initiated in KRNk/g7 mice between 4–5 wk of age underwent a robust acute inflammatory phase, peaked at 6–8 wk, and settled to a chronic phase where ankle deformity predominated and the inflammation was relatively quiescent (Fig. 2 A). In contrast, arthritis in the KRN/G7mTg7k/g7 mice followed a greatly attenuated course both in terms of severity and penetrance. Although 100% of KRNk/g7 mice exhibited symmetrical involvement of all four limbs, KRN/G7mTg7k/g7 mice showed heterogeneous presentation with asymmetrical swelling of one or two isolated limbs in ∼40% of mice. The remainder had swelling on the dorsum of the paws or no synovitis at all. Among those with synovitis, the acute inflammatory phase was foreshortened to 1–2 wk and did not leave any residual limb deformity. Neither control G7mTg7k/g7 nor transgene-negative littermates showed any arthritis (unpublished data).


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)

KRN/G7mTg7k/g7 mice exhibited reduced arthritis and anti-GPI antibodies. (A) Mean ankle thickness ± SD of 6 KRNk/g7 (⋄) and 10 KRN/G7mTg7k/g7 (•) mice. Data are representative of 20 KRNk/g7 and 16 KRN/G7mTg7k/g7 mice derived from 14 separate litters of mice collected over a 6-mo period. (B) Absorbance of anti-GPI ELISA of KRNk/g7 (⋄), KRN/G7mTg7k/g7 (•), G7mTg7k/g7 (▵), and double negative (DN; ○) mice (n = 15, 20, 23, and 12, respectively). Sera from 8-wk-old mice were diluted at 1:100 and serum anti-GPI was detected by ELISA. Each symbol represents an individual mouse. (C) T cell proliferation in response to GPI(281–293). 5 × 105 splenocytes from KRNk/g7 (▪), KRN/G7mTg7k/g7 (•), and transgene-negative (▵) mice were cultured with graded doses of GPI(281–293) peptide with 2 × 105 irradiated H-2k/g7 splenocytes in 96-well round-bottom plates for 72 h with 0.2 μCi [3H]thymidine in the last 18 h. Each point represents the mean of triplicate wells with error bars indicating SD. Data are representative of three independent experiments.
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Related In: Results  -  Collection

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fig2: KRN/G7mTg7k/g7 mice exhibited reduced arthritis and anti-GPI antibodies. (A) Mean ankle thickness ± SD of 6 KRNk/g7 (⋄) and 10 KRN/G7mTg7k/g7 (•) mice. Data are representative of 20 KRNk/g7 and 16 KRN/G7mTg7k/g7 mice derived from 14 separate litters of mice collected over a 6-mo period. (B) Absorbance of anti-GPI ELISA of KRNk/g7 (⋄), KRN/G7mTg7k/g7 (•), G7mTg7k/g7 (▵), and double negative (DN; ○) mice (n = 15, 20, 23, and 12, respectively). Sera from 8-wk-old mice were diluted at 1:100 and serum anti-GPI was detected by ELISA. Each symbol represents an individual mouse. (C) T cell proliferation in response to GPI(281–293). 5 × 105 splenocytes from KRNk/g7 (▪), KRN/G7mTg7k/g7 (•), and transgene-negative (▵) mice were cultured with graded doses of GPI(281–293) peptide with 2 × 105 irradiated H-2k/g7 splenocytes in 96-well round-bottom plates for 72 h with 0.2 μCi [3H]thymidine in the last 18 h. Each point represents the mean of triplicate wells with error bars indicating SD. Data are representative of three independent experiments.
Mentions: KRNk/g7 and KRN/G7mTg7k/g7 mice were followed for the onset and severity of arthritis starting at 4 wk of age. Arthritis initiated in KRNk/g7 mice between 4–5 wk of age underwent a robust acute inflammatory phase, peaked at 6–8 wk, and settled to a chronic phase where ankle deformity predominated and the inflammation was relatively quiescent (Fig. 2 A). In contrast, arthritis in the KRN/G7mTg7k/g7 mice followed a greatly attenuated course both in terms of severity and penetrance. Although 100% of KRNk/g7 mice exhibited symmetrical involvement of all four limbs, KRN/G7mTg7k/g7 mice showed heterogeneous presentation with asymmetrical swelling of one or two isolated limbs in ∼40% of mice. The remainder had swelling on the dorsum of the paws or no synovitis at all. Among those with synovitis, the acute inflammatory phase was foreshortened to 1–2 wk and did not leave any residual limb deformity. Neither control G7mTg7k/g7 nor transgene-negative littermates showed any arthritis (unpublished data).

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