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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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Clonotype+ T cells are deleted in 3A9/G7mTg7 mice. Splenocytes from 3A9 and 3A9/G7mTg7 mice were analyzed by flow cytometry using CD4-PE, CD8-FITC, and 3A9-specific clonotypic antibody 1G12. Dot plot represents CD4 and CD8 expression. Clonotype expression of gated CD4+ T cells are presented in the histograms as solid lines. Background staining of clonotype antibody of transgene-negative mouse is indicated by the dotted lines.
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fig6: Clonotype+ T cells are deleted in 3A9/G7mTg7 mice. Splenocytes from 3A9 and 3A9/G7mTg7 mice were analyzed by flow cytometry using CD4-PE, CD8-FITC, and 3A9-specific clonotypic antibody 1G12. Dot plot represents CD4 and CD8 expression. Clonotype expression of gated CD4+ T cells are presented in the histograms as solid lines. Background staining of clonotype antibody of transgene-negative mouse is indicated by the dotted lines.

Mentions: To determine if the disease phenotype was unique to KRN or was a generalizable phenomenon, we made use of 3A9 TCR Tg that recognizes HEL. Moreover, as HEL is a component of the mHEL/G7m transgene and clonotypic antibody to the 3A9 TCR is available, we could directly examine negative selection of 3A9 in mHEL/G7m. Accordingly, 3A9 TCR Tg mice were crossed to both G7mTg lineages. Consistent with efficient thymic deletion, clonotype+ 3A9 T cells were eliminated in 3A9/G7mTg mice (Fig. 6). As summarized in Table I and Fig. S2 B, which is available at http://www.jem.org/cgi/content/full/jem.20031137/DC1, both lineages of 3A9/G7mTg mice succumbed to disease with wasting, colitis, dermatitis, and autoantibody production starting at 9–10 wk of age. Compared with KRN/G7mTgk/g7 mice, 3A9/G7mTg mice displayed a higher frequency of wasting and colitis (80–94 vs. 50%) and lower frequency of autoantibody production. ANA were produced in 40–60% of 3A9/G7mTg mice and developed at a later time (8–12 wk). Histologically, 3A9/G7mTg mice also displayed multiorgan inflammation, albeit in only a subset of target organs (lungs, liver, and GI tract).


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)

Clonotype+ T cells are deleted in 3A9/G7mTg7 mice. Splenocytes from 3A9 and 3A9/G7mTg7 mice were analyzed by flow cytometry using CD4-PE, CD8-FITC, and 3A9-specific clonotypic antibody 1G12. Dot plot represents CD4 and CD8 expression. Clonotype expression of gated CD4+ T cells are presented in the histograms as solid lines. Background staining of clonotype antibody of transgene-negative mouse is indicated by the dotted lines.
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Related In: Results  -  Collection

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fig6: Clonotype+ T cells are deleted in 3A9/G7mTg7 mice. Splenocytes from 3A9 and 3A9/G7mTg7 mice were analyzed by flow cytometry using CD4-PE, CD8-FITC, and 3A9-specific clonotypic antibody 1G12. Dot plot represents CD4 and CD8 expression. Clonotype expression of gated CD4+ T cells are presented in the histograms as solid lines. Background staining of clonotype antibody of transgene-negative mouse is indicated by the dotted lines.
Mentions: To determine if the disease phenotype was unique to KRN or was a generalizable phenomenon, we made use of 3A9 TCR Tg that recognizes HEL. Moreover, as HEL is a component of the mHEL/G7m transgene and clonotypic antibody to the 3A9 TCR is available, we could directly examine negative selection of 3A9 in mHEL/G7m. Accordingly, 3A9 TCR Tg mice were crossed to both G7mTg lineages. Consistent with efficient thymic deletion, clonotype+ 3A9 T cells were eliminated in 3A9/G7mTg mice (Fig. 6). As summarized in Table I and Fig. S2 B, which is available at http://www.jem.org/cgi/content/full/jem.20031137/DC1, both lineages of 3A9/G7mTg mice succumbed to disease with wasting, colitis, dermatitis, and autoantibody production starting at 9–10 wk of age. Compared with KRN/G7mTgk/g7 mice, 3A9/G7mTg mice displayed a higher frequency of wasting and colitis (80–94 vs. 50%) and lower frequency of autoantibody production. ANA were produced in 40–60% of 3A9/G7mTg mice and developed at a later time (8–12 wk). Histologically, 3A9/G7mTg mice also displayed multiorgan inflammation, albeit in only a subset of target organs (lungs, liver, and GI tract).

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