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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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Wasting disease is transferable by 3A9/G7mTg splenocytes into immunodeficient hosts but not immunocompetent hosts. (A) Unfractionated 3A9 (□) and 3A9/G7m (▪) splenocytes were transferred into B6.AKR mice (n = 3/group). Each data point represents the mean percent of initial weight with error bars indicating SD. (B) Unfractionated 3A9 (○) and 3A9/G7m (•) splenocytes were transferred into RAG1−/− mice (n = 3/group). Each data point represents the mean percent of initial weight with error bars indicating SD. (C) Unfractionated 3A9/G7m (○, ▪, ▴) splenocytes were transferred into RAG1−/− mice. 5 × 105 CD4+ CD25+ (▪) or CD4+ CD25− (▴) splenocytes from 3A9 mice were transferred 24 h before the transfer of 3A9/G7m splenocytes. (D) Unfractionated 3A9 splenocytes (○) or 2 × 107 3A9 CD4+ T cells depleted of CD4+ CD25+ T cells (▪) were transferred into RAG1−/− mice. Each data point represents the mean percent of initial weight of three mice with error bars indicating SD. Data are representative of three independent experiments for A and B and two independent experiments for C and D.
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fig7: Wasting disease is transferable by 3A9/G7mTg splenocytes into immunodeficient hosts but not immunocompetent hosts. (A) Unfractionated 3A9 (□) and 3A9/G7m (▪) splenocytes were transferred into B6.AKR mice (n = 3/group). Each data point represents the mean percent of initial weight with error bars indicating SD. (B) Unfractionated 3A9 (○) and 3A9/G7m (•) splenocytes were transferred into RAG1−/− mice (n = 3/group). Each data point represents the mean percent of initial weight with error bars indicating SD. (C) Unfractionated 3A9/G7m (○, ▪, ▴) splenocytes were transferred into RAG1−/− mice. 5 × 105 CD4+ CD25+ (▪) or CD4+ CD25− (▴) splenocytes from 3A9 mice were transferred 24 h before the transfer of 3A9/G7m splenocytes. (D) Unfractionated 3A9 splenocytes (○) or 2 × 107 3A9 CD4+ T cells depleted of CD4+ CD25+ T cells (▪) were transferred into RAG1−/− mice. Each data point represents the mean percent of initial weight of three mice with error bars indicating SD. Data are representative of three independent experiments for A and B and two independent experiments for C and D.

Mentions: Next, we ascertained whether the disease is transferable by splenocytes. We made use of the 3A9 system where the expression of the cognate antigen can be controlled. Accordingly, unfractionated splenocytes from 3A9/G7mTg mice were transferred into B6.AKR mice. Control mice received unfractionated 3A9 splenocytes. Mice were monitored weekly by clinical appearance and weight. Transfer of 3A9/G7mTg splenocytes into B6.AKR mice did not induce disease. Recipients remained healthy and continued to gain weight compared to control mice that received 3A9 splenocytes (Fig. 7 A). Failure to transfer disease may result from a requirement for mHEL/G7m expression in the host or active suppression by host lymphocytes. As the reduction of CD4+ CD25+ T cells in the KRN/G7mTg7k/g7 mice suggested the loss of Tregs as a mechanism accounting for the systemic autoimmunity seen in these double Tg mice, we repeated the experiment using immunodeficient RAG1−/− hosts. Transfer of 3A9/G7mTg splenocytes into RAG1−/− mice recapitulated the disease phenotype present in 3A9/G7mTg mice. RAG1−/− mice that received 3A9/G7mTg splenocytes displayed steady weight loss with >25% weight loss by 24 d (Fig. 7 B). These mice were moribund and were killed. Histologic examination showed inflammatory changes in the liver, colon, and cecum similar to that seen in double Tg mice (unpublished data). RAG1−/− mice that received 3A9 splenocytes remained healthy. Moreover, the ability to transfer disease into host mice that do not express the mHEL/G7m transgene indicated that anti-HEL T cell response was not required for disease induction consistent with the loss of clonotype+ T cells in 3A9/G7mTg mice. Therefore, the autoreactivity resulted from the specificity encoded by endogenously derived TCRs.


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)

Wasting disease is transferable by 3A9/G7mTg splenocytes into immunodeficient hosts but not immunocompetent hosts. (A) Unfractionated 3A9 (□) and 3A9/G7m (▪) splenocytes were transferred into B6.AKR mice (n = 3/group). Each data point represents the mean percent of initial weight with error bars indicating SD. (B) Unfractionated 3A9 (○) and 3A9/G7m (•) splenocytes were transferred into RAG1−/− mice (n = 3/group). Each data point represents the mean percent of initial weight with error bars indicating SD. (C) Unfractionated 3A9/G7m (○, ▪, ▴) splenocytes were transferred into RAG1−/− mice. 5 × 105 CD4+ CD25+ (▪) or CD4+ CD25− (▴) splenocytes from 3A9 mice were transferred 24 h before the transfer of 3A9/G7m splenocytes. (D) Unfractionated 3A9 splenocytes (○) or 2 × 107 3A9 CD4+ T cells depleted of CD4+ CD25+ T cells (▪) were transferred into RAG1−/− mice. Each data point represents the mean percent of initial weight of three mice with error bars indicating SD. Data are representative of three independent experiments for A and B and two independent experiments for C and D.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2211803&req=5

fig7: Wasting disease is transferable by 3A9/G7mTg splenocytes into immunodeficient hosts but not immunocompetent hosts. (A) Unfractionated 3A9 (□) and 3A9/G7m (▪) splenocytes were transferred into B6.AKR mice (n = 3/group). Each data point represents the mean percent of initial weight with error bars indicating SD. (B) Unfractionated 3A9 (○) and 3A9/G7m (•) splenocytes were transferred into RAG1−/− mice (n = 3/group). Each data point represents the mean percent of initial weight with error bars indicating SD. (C) Unfractionated 3A9/G7m (○, ▪, ▴) splenocytes were transferred into RAG1−/− mice. 5 × 105 CD4+ CD25+ (▪) or CD4+ CD25− (▴) splenocytes from 3A9 mice were transferred 24 h before the transfer of 3A9/G7m splenocytes. (D) Unfractionated 3A9 splenocytes (○) or 2 × 107 3A9 CD4+ T cells depleted of CD4+ CD25+ T cells (▪) were transferred into RAG1−/− mice. Each data point represents the mean percent of initial weight of three mice with error bars indicating SD. Data are representative of three independent experiments for A and B and two independent experiments for C and D.
Mentions: Next, we ascertained whether the disease is transferable by splenocytes. We made use of the 3A9 system where the expression of the cognate antigen can be controlled. Accordingly, unfractionated splenocytes from 3A9/G7mTg mice were transferred into B6.AKR mice. Control mice received unfractionated 3A9 splenocytes. Mice were monitored weekly by clinical appearance and weight. Transfer of 3A9/G7mTg splenocytes into B6.AKR mice did not induce disease. Recipients remained healthy and continued to gain weight compared to control mice that received 3A9 splenocytes (Fig. 7 A). Failure to transfer disease may result from a requirement for mHEL/G7m expression in the host or active suppression by host lymphocytes. As the reduction of CD4+ CD25+ T cells in the KRN/G7mTg7k/g7 mice suggested the loss of Tregs as a mechanism accounting for the systemic autoimmunity seen in these double Tg mice, we repeated the experiment using immunodeficient RAG1−/− hosts. Transfer of 3A9/G7mTg splenocytes into RAG1−/− mice recapitulated the disease phenotype present in 3A9/G7mTg mice. RAG1−/− mice that received 3A9/G7mTg splenocytes displayed steady weight loss with >25% weight loss by 24 d (Fig. 7 B). These mice were moribund and were killed. Histologic examination showed inflammatory changes in the liver, colon, and cecum similar to that seen in double Tg mice (unpublished data). RAG1−/− mice that received 3A9 splenocytes remained healthy. Moreover, the ability to transfer disease into host mice that do not express the mHEL/G7m transgene indicated that anti-HEL T cell response was not required for disease induction consistent with the loss of clonotype+ T cells in 3A9/G7mTg mice. Therefore, the autoreactivity resulted from the specificity encoded by endogenously derived TCRs.

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