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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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mHEL/G7m splenocytes are potent stimulators of KRN T cells. Graded numbers of unfractionated irradiated splenocytes from mHEL/G7mTg7k/g7 (•), nontransgenick/g7 (▵), and NODg7/g7 (□) mice were cultured with 5 × 105 KRNk T cells 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 four independent experiments.
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fig1: mHEL/G7m splenocytes are potent stimulators of KRN T cells. Graded numbers of unfractionated irradiated splenocytes from mHEL/G7mTg7k/g7 (•), nontransgenick/g7 (▵), and NODg7/g7 (□) mice were cultured with 5 × 105 KRNk T cells 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 four independent experiments.

Mentions: Moreover, when we bred G7mTg7 mice to NOD mice to introduce the I-Ag7 molecule, the resultant G7mTg7k/g7 splenocytes provoked vigorous proliferation of KRNk T cells in comparison to the modest response elicited by transgene-negative and NOD splenocytes (Fig. 1). Indeed, expression of the mHEL/G7m transgene augmented T cell stimulation by 1,000-fold relative to that achieved with endogenous GPI, highlighting the enhanced presentation of the KRN TCR ligand through our targeted transgene approach.


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)

mHEL/G7m splenocytes are potent stimulators of KRN T cells. Graded numbers of unfractionated irradiated splenocytes from mHEL/G7mTg7k/g7 (•), nontransgenick/g7 (▵), and NODg7/g7 (□) mice were cultured with 5 × 105 KRNk T cells 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 four independent experiments.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2211803&req=5

fig1: mHEL/G7m splenocytes are potent stimulators of KRN T cells. Graded numbers of unfractionated irradiated splenocytes from mHEL/G7mTg7k/g7 (•), nontransgenick/g7 (▵), and NODg7/g7 (□) mice were cultured with 5 × 105 KRNk T cells 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 four independent experiments.
Mentions: Moreover, when we bred G7mTg7 mice to NOD mice to introduce the I-Ag7 molecule, the resultant G7mTg7k/g7 splenocytes provoked vigorous proliferation of KRNk T cells in comparison to the modest response elicited by transgene-negative and NOD splenocytes (Fig. 1). Indeed, expression of the mHEL/G7m transgene augmented T cell stimulation by 1,000-fold relative to that achieved with endogenous GPI, highlighting the enhanced presentation of the KRN TCR ligand through our targeted transgene approach.

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