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CD4(+) T cells from glutamic acid decarboxylase (GAD)65-specific T cell receptor transgenic mice are not diabetogenic and can delay diabetes transfer.

Tarbell KV, Lee M, Ranheim E, Chao CC, Sanna M, Kim SK, Dickie P, Teyton L, Davis M, McDevitt H - J. Exp. Med. (2002)

Bottom Line: However, the exact role of GAD65-specific T cells in diabetes pathogenesis is unclear.Lymphocytes from these TCR transgenic mice proliferate and make interferon gamma, interleukin (IL)-2, tumor necrosis factor (TNF)-alpha, and IL-10 when stimulated in vitro with GAD65 peptide 286-300, yet these TCR transgenic animals do not spontaneously develop diabetes, and insulitis is virtually undetectable.This data suggests that GAD65 peptide 286-300-specific T cells have disease protective capacity and are not pathogenic.

View Article: PubMed Central - PubMed

Affiliation: Program in Immunology, Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.

ABSTRACT
Glutamic acid decarboxylase (GAD)65 is an early and important antigen in both human diabetes mellitus and the nonobese diabetic (NOD) mouse. However, the exact role of GAD65-specific T cells in diabetes pathogenesis is unclear. T cell responses to GAD65 occur early in diabetes pathogenesis, yet only one GAD65-specific T cell clone of many identified can transfer diabetes. We have generated transgenic mice on the NOD background expressing a T cell receptor (TCR)-specific for peptide epitope 286-300 (p286) of GAD65. These mice have GAD65-specific CD4(+) T cells, as shown by staining with an I-A(g7)(p286) tetramer reagent. Lymphocytes from these TCR transgenic mice proliferate and make interferon gamma, interleukin (IL)-2, tumor necrosis factor (TNF)-alpha, and IL-10 when stimulated in vitro with GAD65 peptide 286-300, yet these TCR transgenic animals do not spontaneously develop diabetes, and insulitis is virtually undetectable. Furthermore, in vitro activated CD4 T cells from GAD 286 TCR transgenic mice express higher levels of CTL-associated antigen (CTLA)-4 than nontransgenic littermates. CD4(+) T cells, or p286-tetramer(+)CD4(+) Tcells, from GAD65 286-300-specific TCR transgenic mice delay diabetes induced in NOD.scid mice by diabetic NOD spleen cells. This data suggests that GAD65 peptide 286-300-specific T cells have disease protective capacity and are not pathogenic.

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Lymphocytes from G286 mice delay transfer of diabetes. Transfer of lymphocytes from recently diabetic NOD females and from G286 mice into NODscid females. The following populations were transferred: (A) 107 diabetic spleen cells (n = 8; circles); or 107 spleen cells from G286 mice (n = 8; squares); or both populations together (n = 8; diamonds). (B) 2 × 106 diabetic spleen cells (circles); 2 × 106 diabetic spleen cells plus 2 × 105 peptide activated CD4+ G286 cells (squares). C) 107 diabetic spleen cells n = 9 (circles); 107 diabetic spleen cells + 107 G286 spleen cells n = 11 (squares); 107 diabetic spleen cells plus 107 G286 spleen cells activated with anti-CD3 plus anti-CD28 n = 9 (diamonds); 107 anti-CD3 activated G286 spleen cells (n = 4; triangles). (D) 107 diabetic spleen cells (n = 11; circles); 107 diabetic spleen cells plus 107 CD3-activated G286 spleen cells (squares); 107 diabetic spleen cells plus 5 × 106 peptide activated G286 CD4+ spleen cells (n = 11; diamonds). (E) 107 diabetic spleen cells (n = 15; circles); 107 diabetic spleen cells plus 107 CD3-activated G286 spleen cells (n = 13; diamonds); 107 diabetic spleen cells plus 107 CD3-activated NOD spleen cells (n = 9; squares).
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fig5: Lymphocytes from G286 mice delay transfer of diabetes. Transfer of lymphocytes from recently diabetic NOD females and from G286 mice into NODscid females. The following populations were transferred: (A) 107 diabetic spleen cells (n = 8; circles); or 107 spleen cells from G286 mice (n = 8; squares); or both populations together (n = 8; diamonds). (B) 2 × 106 diabetic spleen cells (circles); 2 × 106 diabetic spleen cells plus 2 × 105 peptide activated CD4+ G286 cells (squares). C) 107 diabetic spleen cells n = 9 (circles); 107 diabetic spleen cells + 107 G286 spleen cells n = 11 (squares); 107 diabetic spleen cells plus 107 G286 spleen cells activated with anti-CD3 plus anti-CD28 n = 9 (diamonds); 107 anti-CD3 activated G286 spleen cells (n = 4; triangles). (D) 107 diabetic spleen cells (n = 11; circles); 107 diabetic spleen cells plus 107 CD3-activated G286 spleen cells (squares); 107 diabetic spleen cells plus 5 × 106 peptide activated G286 CD4+ spleen cells (n = 11; diamonds). (E) 107 diabetic spleen cells (n = 15; circles); 107 diabetic spleen cells plus 107 CD3-activated G286 spleen cells (n = 13; diamonds); 107 diabetic spleen cells plus 107 CD3-activated NOD spleen cells (n = 9; squares).

Mentions: To determine if this p286-specific CD4+ T cell response has a protective role in diabetes pathogenesis, G286 spleen cells were transferred together with spleen cells from diabetic NOD females. Splenocytes from diabetic NOD females transfer diabetes into 80–100% of NOD.scid recipients within 40 d of transfer (Fig. 5) . By contrast, transfer of splenocytes from G286 mice alone does not transfer diabetes. The addition of G286 splenocytes to diabetogenic cells results in a significant delay in diabetes transfer (Fig. 5 A). In most of the transfer experiments, even the mice which received lymphocytes from G286 mice eventually developed diabetes. This may be because the pathogenic cells from diabetic NOD mice divide faster or take longer to die than the protective G286 cells, allowing the pathogenic cells to overwhelm the G286 cells over time.


CD4(+) T cells from glutamic acid decarboxylase (GAD)65-specific T cell receptor transgenic mice are not diabetogenic and can delay diabetes transfer.

Tarbell KV, Lee M, Ranheim E, Chao CC, Sanna M, Kim SK, Dickie P, Teyton L, Davis M, McDevitt H - J. Exp. Med. (2002)

Lymphocytes from G286 mice delay transfer of diabetes. Transfer of lymphocytes from recently diabetic NOD females and from G286 mice into NODscid females. The following populations were transferred: (A) 107 diabetic spleen cells (n = 8; circles); or 107 spleen cells from G286 mice (n = 8; squares); or both populations together (n = 8; diamonds). (B) 2 × 106 diabetic spleen cells (circles); 2 × 106 diabetic spleen cells plus 2 × 105 peptide activated CD4+ G286 cells (squares). C) 107 diabetic spleen cells n = 9 (circles); 107 diabetic spleen cells + 107 G286 spleen cells n = 11 (squares); 107 diabetic spleen cells plus 107 G286 spleen cells activated with anti-CD3 plus anti-CD28 n = 9 (diamonds); 107 anti-CD3 activated G286 spleen cells (n = 4; triangles). (D) 107 diabetic spleen cells (n = 11; circles); 107 diabetic spleen cells plus 107 CD3-activated G286 spleen cells (squares); 107 diabetic spleen cells plus 5 × 106 peptide activated G286 CD4+ spleen cells (n = 11; diamonds). (E) 107 diabetic spleen cells (n = 15; circles); 107 diabetic spleen cells plus 107 CD3-activated G286 spleen cells (n = 13; diamonds); 107 diabetic spleen cells plus 107 CD3-activated NOD spleen cells (n = 9; squares).
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Related In: Results  -  Collection

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fig5: Lymphocytes from G286 mice delay transfer of diabetes. Transfer of lymphocytes from recently diabetic NOD females and from G286 mice into NODscid females. The following populations were transferred: (A) 107 diabetic spleen cells (n = 8; circles); or 107 spleen cells from G286 mice (n = 8; squares); or both populations together (n = 8; diamonds). (B) 2 × 106 diabetic spleen cells (circles); 2 × 106 diabetic spleen cells plus 2 × 105 peptide activated CD4+ G286 cells (squares). C) 107 diabetic spleen cells n = 9 (circles); 107 diabetic spleen cells + 107 G286 spleen cells n = 11 (squares); 107 diabetic spleen cells plus 107 G286 spleen cells activated with anti-CD3 plus anti-CD28 n = 9 (diamonds); 107 anti-CD3 activated G286 spleen cells (n = 4; triangles). (D) 107 diabetic spleen cells (n = 11; circles); 107 diabetic spleen cells plus 107 CD3-activated G286 spleen cells (squares); 107 diabetic spleen cells plus 5 × 106 peptide activated G286 CD4+ spleen cells (n = 11; diamonds). (E) 107 diabetic spleen cells (n = 15; circles); 107 diabetic spleen cells plus 107 CD3-activated G286 spleen cells (n = 13; diamonds); 107 diabetic spleen cells plus 107 CD3-activated NOD spleen cells (n = 9; squares).
Mentions: To determine if this p286-specific CD4+ T cell response has a protective role in diabetes pathogenesis, G286 spleen cells were transferred together with spleen cells from diabetic NOD females. Splenocytes from diabetic NOD females transfer diabetes into 80–100% of NOD.scid recipients within 40 d of transfer (Fig. 5) . By contrast, transfer of splenocytes from G286 mice alone does not transfer diabetes. The addition of G286 splenocytes to diabetogenic cells results in a significant delay in diabetes transfer (Fig. 5 A). In most of the transfer experiments, even the mice which received lymphocytes from G286 mice eventually developed diabetes. This may be because the pathogenic cells from diabetic NOD mice divide faster or take longer to die than the protective G286 cells, allowing the pathogenic cells to overwhelm the G286 cells over time.

Bottom Line: However, the exact role of GAD65-specific T cells in diabetes pathogenesis is unclear.Lymphocytes from these TCR transgenic mice proliferate and make interferon gamma, interleukin (IL)-2, tumor necrosis factor (TNF)-alpha, and IL-10 when stimulated in vitro with GAD65 peptide 286-300, yet these TCR transgenic animals do not spontaneously develop diabetes, and insulitis is virtually undetectable.This data suggests that GAD65 peptide 286-300-specific T cells have disease protective capacity and are not pathogenic.

View Article: PubMed Central - PubMed

Affiliation: Program in Immunology, Department of Pathology, Stanford University School of Medicine, Stanford, CA 94305, USA.

ABSTRACT
Glutamic acid decarboxylase (GAD)65 is an early and important antigen in both human diabetes mellitus and the nonobese diabetic (NOD) mouse. However, the exact role of GAD65-specific T cells in diabetes pathogenesis is unclear. T cell responses to GAD65 occur early in diabetes pathogenesis, yet only one GAD65-specific T cell clone of many identified can transfer diabetes. We have generated transgenic mice on the NOD background expressing a T cell receptor (TCR)-specific for peptide epitope 286-300 (p286) of GAD65. These mice have GAD65-specific CD4(+) T cells, as shown by staining with an I-A(g7)(p286) tetramer reagent. Lymphocytes from these TCR transgenic mice proliferate and make interferon gamma, interleukin (IL)-2, tumor necrosis factor (TNF)-alpha, and IL-10 when stimulated in vitro with GAD65 peptide 286-300, yet these TCR transgenic animals do not spontaneously develop diabetes, and insulitis is virtually undetectable. Furthermore, in vitro activated CD4 T cells from GAD 286 TCR transgenic mice express higher levels of CTL-associated antigen (CTLA)-4 than nontransgenic littermates. CD4(+) T cells, or p286-tetramer(+)CD4(+) Tcells, from GAD65 286-300-specific TCR transgenic mice delay diabetes induced in NOD.scid mice by diabetic NOD spleen cells. This data suggests that GAD65 peptide 286-300-specific T cells have disease protective capacity and are not pathogenic.

Show MeSH
Related in: MedlinePlus