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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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BDC2.5 CD25+ CD4+ T cells can still regulate diabetes when given after diabetogenic cells. (A) NOD.scid females were injected with 8 × 106 diabetic spleen cells and 11 d later were injected with either PBS or the indicated number of DC-expanded CD25+ CD4+ T cells from BDC2.5 mice. The difference between diabetic spleen alone to diabetic spleen plus 105 or 104 DC-expanded CD25+ CD4+ cells was significant (P = 0.002). (B) As in A, except 107 diabetic spleen cells were added 15 d before the indicated number of DC-expanded CD25+ CD4+ T cells from BDC2.5 mice. The p-value for diabetic spleen alone versus adding 105 BDC2.5 regulatory T cells is 0.055 and versus adding 104 BDC2.5 regulatory T cells is 0.0595. The number of mice in each group is indicated in parentheses.
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fig7: BDC2.5 CD25+ CD4+ T cells can still regulate diabetes when given after diabetogenic cells. (A) NOD.scid females were injected with 8 × 106 diabetic spleen cells and 11 d later were injected with either PBS or the indicated number of DC-expanded CD25+ CD4+ T cells from BDC2.5 mice. The difference between diabetic spleen alone to diabetic spleen plus 105 or 104 DC-expanded CD25+ CD4+ cells was significant (P = 0.002). (B) As in A, except 107 diabetic spleen cells were added 15 d before the indicated number of DC-expanded CD25+ CD4+ T cells from BDC2.5 mice. The p-value for diabetic spleen alone versus adding 105 BDC2.5 regulatory T cells is 0.055 and versus adding 104 BDC2.5 regulatory T cells is 0.0595. The number of mice in each group is indicated in parentheses.

Mentions: One feature of the NOD.scid system is that T cells, when injected into a lymphopenic host, undergo antigen-independent, homeostatic proliferation. To lessen the effect of such proliferation on the CD25+ CD4+ T cells, the latter were injected after the diabetogenic spleen cells. Even when given 11 d after the diabetogenic cells, as few as 12,000 DC-expanded, BDC2.5 CD25+ CD4+ T cells prevented diabetes development (Fig. 7 A). When given 15 d after diabetogenic cells, 104 cells significantly delay diabetes (Fig. 7 B). At these time points, by FACS® staining for CD4+ cells, we showed that lymphocytes from the diabetic mice had repopulated the lymphoid organs, and even entered the pancreas (not depicted). Therefore, CD25+ CD4+ T cells can block diabetes even after the diabetogenic cells have been given time to occupy the lymphoid compartments, and initiate diabetes pathogenesis. Further studies will be needed to check the capacity of DC-expanded, antigen-specific CD25+ CD4+ T cells to suppress disease under nonhomeostatic conditions.


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)

BDC2.5 CD25+ CD4+ T cells can still regulate diabetes when given after diabetogenic cells. (A) NOD.scid females were injected with 8 × 106 diabetic spleen cells and 11 d later were injected with either PBS or the indicated number of DC-expanded CD25+ CD4+ T cells from BDC2.5 mice. The difference between diabetic spleen alone to diabetic spleen plus 105 or 104 DC-expanded CD25+ CD4+ cells was significant (P = 0.002). (B) As in A, except 107 diabetic spleen cells were added 15 d before the indicated number of DC-expanded CD25+ CD4+ T cells from BDC2.5 mice. The p-value for diabetic spleen alone versus adding 105 BDC2.5 regulatory T cells is 0.055 and versus adding 104 BDC2.5 regulatory T cells is 0.0595. The number of mice in each group is indicated in parentheses.
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fig7: BDC2.5 CD25+ CD4+ T cells can still regulate diabetes when given after diabetogenic cells. (A) NOD.scid females were injected with 8 × 106 diabetic spleen cells and 11 d later were injected with either PBS or the indicated number of DC-expanded CD25+ CD4+ T cells from BDC2.5 mice. The difference between diabetic spleen alone to diabetic spleen plus 105 or 104 DC-expanded CD25+ CD4+ cells was significant (P = 0.002). (B) As in A, except 107 diabetic spleen cells were added 15 d before the indicated number of DC-expanded CD25+ CD4+ T cells from BDC2.5 mice. The p-value for diabetic spleen alone versus adding 105 BDC2.5 regulatory T cells is 0.055 and versus adding 104 BDC2.5 regulatory T cells is 0.0595. The number of mice in each group is indicated in parentheses.
Mentions: One feature of the NOD.scid system is that T cells, when injected into a lymphopenic host, undergo antigen-independent, homeostatic proliferation. To lessen the effect of such proliferation on the CD25+ CD4+ T cells, the latter were injected after the diabetogenic spleen cells. Even when given 11 d after the diabetogenic cells, as few as 12,000 DC-expanded, BDC2.5 CD25+ CD4+ T cells prevented diabetes development (Fig. 7 A). When given 15 d after diabetogenic cells, 104 cells significantly delay diabetes (Fig. 7 B). At these time points, by FACS® staining for CD4+ cells, we showed that lymphocytes from the diabetic mice had repopulated the lymphoid organs, and even entered the pancreas (not depicted). Therefore, CD25+ CD4+ T cells can block diabetes even after the diabetogenic cells have been given time to occupy the lymphoid compartments, and initiate diabetes pathogenesis. Further studies will be needed to check the capacity of DC-expanded, antigen-specific CD25+ CD4+ T cells to suppress disease under nonhomeostatic conditions.

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