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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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Incidence of diabetes and insulitis in G286 mice. (A) Diabetes incidence in female G286 (circles, n = 6) or NOD littermates (squares, n = 9). (B) Insulitis in 17-wk-old (left) or 30-wk-old (right) female G286 mice. Islets were scored as either no insulitis, periinsulitis, or intrainsulitis. A total of 42 and 160 islets were scored in the 17-wk-old and 30-wk-old mice, respectively. Salivary gland tissue sections from 22-wk-old NOD (C) and 23-wk-old G286 (D) mice. Original magnification is 40× for the large picture, and the inset (location in large picture indicated by the black box) shows one focus of infiltrating lymphocytes at an original magnification of 200×.
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fig3: Incidence of diabetes and insulitis in G286 mice. (A) Diabetes incidence in female G286 (circles, n = 6) or NOD littermates (squares, n = 9). (B) Insulitis in 17-wk-old (left) or 30-wk-old (right) female G286 mice. Islets were scored as either no insulitis, periinsulitis, or intrainsulitis. A total of 42 and 160 islets were scored in the 17-wk-old and 30-wk-old mice, respectively. Salivary gland tissue sections from 22-wk-old NOD (C) and 23-wk-old G286 (D) mice. Original magnification is 40× for the large picture, and the inset (location in large picture indicated by the black box) shows one focus of infiltrating lymphocytes at an original magnification of 200×.

Mentions: G286 females and transgene negative littermates were followed for 30 wk for diabetes. 80% of the nontransgenic and 0% of the G286 mice developed diabetes (Fig. 3 A). At 30 wk, the six G286 mice and two remaining nondiabetic nontransgenic mice were killed and insulitis assessed. Only 10% of islets in transgenic mice displayed any insulitis, whereas both of the nontransgenics had severe insulitis in the few islets that remained. A similar pattern of insulitis was seen in 17-wk-old mice (Fig. 3 B). Subsequently, none of the dozens of G286 mice used for other experiments have developed diabetes, and the second G286 transgenic B line also does not develop diabetes. Because mice which express an unrelated transgenic TCR can still develop diabetes (13, 14), and because G286 mice do not develop diabetes, it is likely that the p286-specific TCR plays a protective role in diabetes pathogenesis. In addition, both NOD and G286 mice develop lymphocytic infiltration in the salivary glands, although sialtis in G286 mice is less severe (Fig. 3 C). This suggests that the lack of inflammatory infiltration in the pancreas of G286 mice may be due to specific suppression of islet-specific responses and not due to the absence of a pathogenic repertoire or to a general immune disregulation.


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)

Incidence of diabetes and insulitis in G286 mice. (A) Diabetes incidence in female G286 (circles, n = 6) or NOD littermates (squares, n = 9). (B) Insulitis in 17-wk-old (left) or 30-wk-old (right) female G286 mice. Islets were scored as either no insulitis, periinsulitis, or intrainsulitis. A total of 42 and 160 islets were scored in the 17-wk-old and 30-wk-old mice, respectively. Salivary gland tissue sections from 22-wk-old NOD (C) and 23-wk-old G286 (D) mice. Original magnification is 40× for the large picture, and the inset (location in large picture indicated by the black box) shows one focus of infiltrating lymphocytes at an original magnification of 200×.
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getmorefigures.php?uid=PMC2196059&req=5

fig3: Incidence of diabetes and insulitis in G286 mice. (A) Diabetes incidence in female G286 (circles, n = 6) or NOD littermates (squares, n = 9). (B) Insulitis in 17-wk-old (left) or 30-wk-old (right) female G286 mice. Islets were scored as either no insulitis, periinsulitis, or intrainsulitis. A total of 42 and 160 islets were scored in the 17-wk-old and 30-wk-old mice, respectively. Salivary gland tissue sections from 22-wk-old NOD (C) and 23-wk-old G286 (D) mice. Original magnification is 40× for the large picture, and the inset (location in large picture indicated by the black box) shows one focus of infiltrating lymphocytes at an original magnification of 200×.
Mentions: G286 females and transgene negative littermates were followed for 30 wk for diabetes. 80% of the nontransgenic and 0% of the G286 mice developed diabetes (Fig. 3 A). At 30 wk, the six G286 mice and two remaining nondiabetic nontransgenic mice were killed and insulitis assessed. Only 10% of islets in transgenic mice displayed any insulitis, whereas both of the nontransgenics had severe insulitis in the few islets that remained. A similar pattern of insulitis was seen in 17-wk-old mice (Fig. 3 B). Subsequently, none of the dozens of G286 mice used for other experiments have developed diabetes, and the second G286 transgenic B line also does not develop diabetes. Because mice which express an unrelated transgenic TCR can still develop diabetes (13, 14), and because G286 mice do not develop diabetes, it is likely that the p286-specific TCR plays a protective role in diabetes pathogenesis. In addition, both NOD and G286 mice develop lymphocytic infiltration in the salivary glands, although sialtis in G286 mice is less severe (Fig. 3 C). This suggests that the lack of inflammatory infiltration in the pancreas of G286 mice may be due to specific suppression of islet-specific responses and not due to the absence of a pathogenic repertoire or to a general immune disregulation.

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