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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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Expanded CD25+ CD4+ T cells function in vivo to suppress development of diabetes. (A) 4–6-wk-old NOD.BDC2.5 mice were given cyclophosphamide i.p. 3 d later, either 5 × 105 DC-expanded CD25+ CD4+ T cells or CD25− CD4+ cells were injected i.v. (B) NOD.scid females were injected with 3 × 106 spleen cells from a diabetic NOD female and either nothing or the indicated numbers of DC-expanded CD25+ CD4+ T cells or 3 × 105 CD25− CD4+ cells from BDC2.5 mice. (C) NOD.scid females were injected with either 4 × 105 CD25− CD4+ cells from BDC2.5 mice, or 8 × 106 spleen cells from a diabetic NOD female and either nothing or the indicated numbers of DC-expanded CD25+ CD4+ T cells from BDC2.5 mice. The difference between diabetic spleen alone to diabetic spleen plus 500 CD25+ CD4+ cells was significant (P = 0.002), as was diabetic spleen to diabetic spleen plus 5,000 CD25+ CD4+ cells (P = 0.002). One representative result from two experiments is shown. (D) NOD.scid females were injected with 8 × 106 diabetic spleen cells alone or with 105 freshly isolated or DC/αCD3-expanded CD25+ CD4+ T cells from NOD mice. The number of mice in each group is indicated in parentheses.
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fig5: Expanded CD25+ CD4+ T cells function in vivo to suppress development of diabetes. (A) 4–6-wk-old NOD.BDC2.5 mice were given cyclophosphamide i.p. 3 d later, either 5 × 105 DC-expanded CD25+ CD4+ T cells or CD25− CD4+ cells were injected i.v. (B) NOD.scid females were injected with 3 × 106 spleen cells from a diabetic NOD female and either nothing or the indicated numbers of DC-expanded CD25+ CD4+ T cells or 3 × 105 CD25− CD4+ cells from BDC2.5 mice. (C) NOD.scid females were injected with either 4 × 105 CD25− CD4+ cells from BDC2.5 mice, or 8 × 106 spleen cells from a diabetic NOD female and either nothing or the indicated numbers of DC-expanded CD25+ CD4+ T cells from BDC2.5 mice. The difference between diabetic spleen alone to diabetic spleen plus 500 CD25+ CD4+ cells was significant (P = 0.002), as was diabetic spleen to diabetic spleen plus 5,000 CD25+ CD4+ cells (P = 0.002). One representative result from two experiments is shown. (D) NOD.scid females were injected with 8 × 106 diabetic spleen cells alone or with 105 freshly isolated or DC/αCD3-expanded CD25+ CD4+ T cells from NOD mice. The number of mice in each group is indicated in parentheses.

Mentions: A critical in vivo function for CD25+ CD4+ T cells is the prevention of autoimmunity. Therefore, we wanted to determine if BDC2.5 CD25+ CD4+ T cells expanded in vitro with DCs and antigen could inhibit the development of diabetes. The first model of diabetes we used was one in which the pathogenic T cells to be suppressed were of the same BDC2.5 specificity. As expected from previous work (41), most BDC2.5 mice on the NOD background did not develop diabetes, but when young BDC2.5 NOD mice were given one injection of cyclophosphamide, diabetes developed 4–7 d later in 100% of the mice. To suppress this diabetes induction, 3 d after cyclophosphamide treatment, we injected BDC2.5.NOD mice with DC-expanded CD25+ CD4+ T cells from BDC2.5 mice. In two experiments, this resulted in a delay of diabetes onset and a reduced diabetes incidence. In contrast, injection of DC-expanded CD25− CD4+ from BDC2.5 mice had little effect on diabetes development (Fig. 5 A). These results show that the DC-expanded suppressor T cells are able to suppress autoimmunity even when the disease is developing rapidly.


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)

Expanded CD25+ CD4+ T cells function in vivo to suppress development of diabetes. (A) 4–6-wk-old NOD.BDC2.5 mice were given cyclophosphamide i.p. 3 d later, either 5 × 105 DC-expanded CD25+ CD4+ T cells or CD25− CD4+ cells were injected i.v. (B) NOD.scid females were injected with 3 × 106 spleen cells from a diabetic NOD female and either nothing or the indicated numbers of DC-expanded CD25+ CD4+ T cells or 3 × 105 CD25− CD4+ cells from BDC2.5 mice. (C) NOD.scid females were injected with either 4 × 105 CD25− CD4+ cells from BDC2.5 mice, or 8 × 106 spleen cells from a diabetic NOD female and either nothing or the indicated numbers of DC-expanded CD25+ CD4+ T cells from BDC2.5 mice. The difference between diabetic spleen alone to diabetic spleen plus 500 CD25+ CD4+ cells was significant (P = 0.002), as was diabetic spleen to diabetic spleen plus 5,000 CD25+ CD4+ cells (P = 0.002). One representative result from two experiments is shown. (D) NOD.scid females were injected with 8 × 106 diabetic spleen cells alone or with 105 freshly isolated or DC/αCD3-expanded CD25+ CD4+ T cells from NOD mice. The number of mice in each group is indicated in parentheses.
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Related In: Results  -  Collection

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fig5: Expanded CD25+ CD4+ T cells function in vivo to suppress development of diabetes. (A) 4–6-wk-old NOD.BDC2.5 mice were given cyclophosphamide i.p. 3 d later, either 5 × 105 DC-expanded CD25+ CD4+ T cells or CD25− CD4+ cells were injected i.v. (B) NOD.scid females were injected with 3 × 106 spleen cells from a diabetic NOD female and either nothing or the indicated numbers of DC-expanded CD25+ CD4+ T cells or 3 × 105 CD25− CD4+ cells from BDC2.5 mice. (C) NOD.scid females were injected with either 4 × 105 CD25− CD4+ cells from BDC2.5 mice, or 8 × 106 spleen cells from a diabetic NOD female and either nothing or the indicated numbers of DC-expanded CD25+ CD4+ T cells from BDC2.5 mice. The difference between diabetic spleen alone to diabetic spleen plus 500 CD25+ CD4+ cells was significant (P = 0.002), as was diabetic spleen to diabetic spleen plus 5,000 CD25+ CD4+ cells (P = 0.002). One representative result from two experiments is shown. (D) NOD.scid females were injected with 8 × 106 diabetic spleen cells alone or with 105 freshly isolated or DC/αCD3-expanded CD25+ CD4+ T cells from NOD mice. The number of mice in each group is indicated in parentheses.
Mentions: A critical in vivo function for CD25+ CD4+ T cells is the prevention of autoimmunity. Therefore, we wanted to determine if BDC2.5 CD25+ CD4+ T cells expanded in vitro with DCs and antigen could inhibit the development of diabetes. The first model of diabetes we used was one in which the pathogenic T cells to be suppressed were of the same BDC2.5 specificity. As expected from previous work (41), most BDC2.5 mice on the NOD background did not develop diabetes, but when young BDC2.5 NOD mice were given one injection of cyclophosphamide, diabetes developed 4–7 d later in 100% of the mice. To suppress this diabetes induction, 3 d after cyclophosphamide treatment, we injected BDC2.5.NOD mice with DC-expanded CD25+ CD4+ T cells from BDC2.5 mice. In two experiments, this resulted in a delay of diabetes onset and a reduced diabetes incidence. In contrast, injection of DC-expanded CD25− CD4+ from BDC2.5 mice had little effect on diabetes development (Fig. 5 A). These results show that the DC-expanded suppressor T cells are able to suppress autoimmunity even when the disease is developing rapidly.

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