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CD25+ CD4+ T cells, expanded with dendritic cells presenting a single autoantigenic peptide, suppress autoimmune diabetes.

Tarbell KV, Yamazaki S, Olson K, Toy P, Steinman RM - J. Exp. Med. (2004)

Bottom Line: The expanded CD25+ CD4+ BDC2.5 T cells were effective even if administered 14 d after the diabetogenic T cells.Our data indicate that DCs can generate CD25+ CD4+ T cells that suppress autoimmune disease in vivo.This might be harnessed as a new avenue for immunotherapy, especially because CD25+ CD4+ regulatory cells responsive to a single autoantigen can inhibit diabetes mediated by reactivity to multiple antigens.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Cellular Physiology and Immunology, The Rockefeller University, 1230 York Avenue, New York, NY 10021, USA.

ABSTRACT
In the nonobese diabetic (NOD) mouse model of type 1 diabetes, the immune system recognizes many autoantigens expressed in pancreatic islet beta cells. To silence autoimmunity, we used dendritic cells (DCs) from NOD mice to expand CD25+ CD4+ suppressor T cells from BDC2.5 mice, which are specific for a single islet autoantigen. The expanded T cells were more suppressive in vitro than their freshly isolated counterparts, indicating that DCs from autoimmune mice can increase the number and function of antigen-specific, CD25+ CD4+ regulatory T cells. Importantly, only 5,000 expanded CD25+ CD4+ BDC2.5 T cells could block autoimmunity caused by diabetogenic T cells in NOD mice, whereas 10(5) polyclonal, CD25+ CD4+ T cells from NOD mice were inactive. When islets were examined in treated mice, insulitis development was blocked at early (3 wk) but not later (11 wk) time points. The expanded CD25+ CD4+ BDC2.5 T cells were effective even if administered 14 d after the diabetogenic T cells. Our data indicate that DCs can generate CD25+ CD4+ T cells that suppress autoimmune disease in vivo. This might be harnessed as a new avenue for immunotherapy, especially because CD25+ CD4+ regulatory cells responsive to a single autoantigen can inhibit diabetes mediated by reactivity to multiple antigens.

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Protected mice have lymphocytic infiltrates in the pancreas. (A) Pancreata from mice that did not develop diabetes by day 80 after transfer in the experiment shown in Fig. 5 C were scored for insulitis. 150 islets from 5 mice were scored from the group that received 50,000 DC-expanded BDC CD25+ CD4+ T cells, and 48 islets from 2 mice were scored from the group that received 5,000 cells. (B) Representative fields for a mouse from the group that received 5,000 (top) or 50,000 (bottom) suppressor T cells. Large field is 5×; inset is 20×. (C) In a separate experiment, pancreata from mice 28 d after transfer were scored for insulitis. At least 50 islets from 2–3 mice were scored from each group.
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fig6: Protected mice have lymphocytic infiltrates in the pancreas. (A) Pancreata from mice that did not develop diabetes by day 80 after transfer in the experiment shown in Fig. 5 C were scored for insulitis. 150 islets from 5 mice were scored from the group that received 50,000 DC-expanded BDC CD25+ CD4+ T cells, and 48 islets from 2 mice were scored from the group that received 5,000 cells. (B) Representative fields for a mouse from the group that received 5,000 (top) or 50,000 (bottom) suppressor T cells. Large field is 5×; inset is 20×. (C) In a separate experiment, pancreata from mice 28 d after transfer were scored for insulitis. At least 50 islets from 2–3 mice were scored from each group.

Mentions: To determine at which stage disease was blocked in NOD.scid mice protected from diabetes by small numbers of BDC2.5-specific CD25+ CD4+ T cells, pancreata were isolated from those mice that still had normal glucose levels at the end of the experiment shown in Fig. 5 C (80 d after transfer). Insulitis was scored from hematoxylin and eosin–stained sections. The mice from the groups that received 5,000 or 50,000 BDC2.5-specific CD25+ CD4+ T cells (the latter group were all diabetes free), had lymphocytic infiltrates in half of the islets scored (Fig. 6 A). A representative field from both protected groups is shown (Fig. 6 B). In a separate transfer experiment, pancreata were isolated from mice earlier on, at 23 or 28 d after transfer of the diabetogenic and regulatory cells. At this earlier time point, the mice that had received only the diabetogenic cells had some insulitis, but those that had also received BDC2.5 regulatory cells lacked lymphocytic infiltrate in the islets (Fig. 6 C). This indicates that protected mice can progress past the initiation of islet inflammation, checkpoint I, but the kinetics of insulitis is slower than in the absence of regulatory cells.


CD25+ CD4+ T cells, expanded with dendritic cells presenting a single autoantigenic peptide, suppress autoimmune diabetes.

Tarbell KV, Yamazaki S, Olson K, Toy P, Steinman RM - J. Exp. Med. (2004)

Protected mice have lymphocytic infiltrates in the pancreas. (A) Pancreata from mice that did not develop diabetes by day 80 after transfer in the experiment shown in Fig. 5 C were scored for insulitis. 150 islets from 5 mice were scored from the group that received 50,000 DC-expanded BDC CD25+ CD4+ T cells, and 48 islets from 2 mice were scored from the group that received 5,000 cells. (B) Representative fields for a mouse from the group that received 5,000 (top) or 50,000 (bottom) suppressor T cells. Large field is 5×; inset is 20×. (C) In a separate experiment, pancreata from mice 28 d after transfer were scored for insulitis. At least 50 islets from 2–3 mice were scored from each group.
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fig6: Protected mice have lymphocytic infiltrates in the pancreas. (A) Pancreata from mice that did not develop diabetes by day 80 after transfer in the experiment shown in Fig. 5 C were scored for insulitis. 150 islets from 5 mice were scored from the group that received 50,000 DC-expanded BDC CD25+ CD4+ T cells, and 48 islets from 2 mice were scored from the group that received 5,000 cells. (B) Representative fields for a mouse from the group that received 5,000 (top) or 50,000 (bottom) suppressor T cells. Large field is 5×; inset is 20×. (C) In a separate experiment, pancreata from mice 28 d after transfer were scored for insulitis. At least 50 islets from 2–3 mice were scored from each group.
Mentions: To determine at which stage disease was blocked in NOD.scid mice protected from diabetes by small numbers of BDC2.5-specific CD25+ CD4+ T cells, pancreata were isolated from those mice that still had normal glucose levels at the end of the experiment shown in Fig. 5 C (80 d after transfer). Insulitis was scored from hematoxylin and eosin–stained sections. The mice from the groups that received 5,000 or 50,000 BDC2.5-specific CD25+ CD4+ T cells (the latter group were all diabetes free), had lymphocytic infiltrates in half of the islets scored (Fig. 6 A). A representative field from both protected groups is shown (Fig. 6 B). In a separate transfer experiment, pancreata were isolated from mice earlier on, at 23 or 28 d after transfer of the diabetogenic and regulatory cells. At this earlier time point, the mice that had received only the diabetogenic cells had some insulitis, but those that had also received BDC2.5 regulatory cells lacked lymphocytic infiltrate in the islets (Fig. 6 C). This indicates that protected mice can progress past the initiation of islet inflammation, checkpoint I, but the kinetics of insulitis is slower than in the absence of regulatory cells.

Bottom Line: The expanded CD25+ CD4+ BDC2.5 T cells were effective even if administered 14 d after the diabetogenic T cells.Our data indicate that DCs can generate CD25+ CD4+ T cells that suppress autoimmune disease in vivo.This might be harnessed as a new avenue for immunotherapy, especially because CD25+ CD4+ regulatory cells responsive to a single autoantigen can inhibit diabetes mediated by reactivity to multiple antigens.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Cellular Physiology and Immunology, The Rockefeller University, 1230 York Avenue, New York, NY 10021, USA.

ABSTRACT
In the nonobese diabetic (NOD) mouse model of type 1 diabetes, the immune system recognizes many autoantigens expressed in pancreatic islet beta cells. To silence autoimmunity, we used dendritic cells (DCs) from NOD mice to expand CD25+ CD4+ suppressor T cells from BDC2.5 mice, which are specific for a single islet autoantigen. The expanded T cells were more suppressive in vitro than their freshly isolated counterparts, indicating that DCs from autoimmune mice can increase the number and function of antigen-specific, CD25+ CD4+ regulatory T cells. Importantly, only 5,000 expanded CD25+ CD4+ BDC2.5 T cells could block autoimmunity caused by diabetogenic T cells in NOD mice, whereas 10(5) polyclonal, CD25+ CD4+ T cells from NOD mice were inactive. When islets were examined in treated mice, insulitis development was blocked at early (3 wk) but not later (11 wk) time points. The expanded CD25+ CD4+ BDC2.5 T cells were effective even if administered 14 d after the diabetogenic T cells. Our data indicate that DCs can generate CD25+ CD4+ T cells that suppress autoimmune disease in vivo. This might be harnessed as a new avenue for immunotherapy, especially because CD25+ CD4+ regulatory cells responsive to a single autoantigen can inhibit diabetes mediated by reactivity to multiple antigens.

Show MeSH
Related in: MedlinePlus