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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 proliferate in vivo. CFSE-labeled BDC2.5 CD25− CD4+ (left) or CD25+ CD4+ (right) T cells were injected into NOD mice. 1 d later, either DCs without antigen (top) or BDC peptide–pulsed DCs (middle and bottom) were injected s.c. 3 d after antigen delivery, the injected >1,000 CFSE-labeled clonotype+ cells from draining (top and middle) or distal (bottom) lymph nodes were assessed for proliferation by flow cytometry, gating on CD4+ lymphocytes. The percentages in the dividing and nondivding populations of clonotype+ cells is shown.
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fig3: BDC2.5 CD25+ CD4+ T cells proliferate in vivo. CFSE-labeled BDC2.5 CD25− CD4+ (left) or CD25+ CD4+ (right) T cells were injected into NOD mice. 1 d later, either DCs without antigen (top) or BDC peptide–pulsed DCs (middle and bottom) were injected s.c. 3 d after antigen delivery, the injected >1,000 CFSE-labeled clonotype+ cells from draining (top and middle) or distal (bottom) lymph nodes were assessed for proliferation by flow cytometry, gating on CD4+ lymphocytes. The percentages in the dividing and nondivding populations of clonotype+ cells is shown.

Mentions: To determine if DCs also can induce proliferation of CD25+ CD4+ T cells in vivo, we purified CD25+ CD4+ T cells from BDC2.5 mice, labeled them with CFSE before injection into NOD mice, and 1 d later, we s.c. injected mature marrow–derived DCs that had been pulsed (or not pulsed as control) with BDC peptide. We assessed proliferation 3 d later by progressive halving of the amount of CFSE per T cell. The CD25+ CD4+ T cells proliferated, with up to six divisions per cell, in the draining lymph nodes of mice that received BDC peptide–pulsed DCs, but not in mice that received PBS or DCs alone (Fig. 3 and not depicted). We observed similar proliferative responses with control CD25− CD4+ cells, but CFSE was not diluted in either CD25+ or CD25− CD4+ cells in the distal lymph nodes of mice receiving either pulsed or unpulsed DCs (Fig. 3). Therefore, DCs are able to induce the proliferation of CD25+ CD4+ T cells from an autoimmune strain in vivo.


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 proliferate in vivo. CFSE-labeled BDC2.5 CD25− CD4+ (left) or CD25+ CD4+ (right) T cells were injected into NOD mice. 1 d later, either DCs without antigen (top) or BDC peptide–pulsed DCs (middle and bottom) were injected s.c. 3 d after antigen delivery, the injected >1,000 CFSE-labeled clonotype+ cells from draining (top and middle) or distal (bottom) lymph nodes were assessed for proliferation by flow cytometry, gating on CD4+ lymphocytes. The percentages in the dividing and nondivding populations of clonotype+ cells is shown.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC2211787&req=5

fig3: BDC2.5 CD25+ CD4+ T cells proliferate in vivo. CFSE-labeled BDC2.5 CD25− CD4+ (left) or CD25+ CD4+ (right) T cells were injected into NOD mice. 1 d later, either DCs without antigen (top) or BDC peptide–pulsed DCs (middle and bottom) were injected s.c. 3 d after antigen delivery, the injected >1,000 CFSE-labeled clonotype+ cells from draining (top and middle) or distal (bottom) lymph nodes were assessed for proliferation by flow cytometry, gating on CD4+ lymphocytes. The percentages in the dividing and nondivding populations of clonotype+ cells is shown.
Mentions: To determine if DCs also can induce proliferation of CD25+ CD4+ T cells in vivo, we purified CD25+ CD4+ T cells from BDC2.5 mice, labeled them with CFSE before injection into NOD mice, and 1 d later, we s.c. injected mature marrow–derived DCs that had been pulsed (or not pulsed as control) with BDC peptide. We assessed proliferation 3 d later by progressive halving of the amount of CFSE per T cell. The CD25+ CD4+ T cells proliferated, with up to six divisions per cell, in the draining lymph nodes of mice that received BDC peptide–pulsed DCs, but not in mice that received PBS or DCs alone (Fig. 3 and not depicted). We observed similar proliferative responses with control CD25− CD4+ cells, but CFSE was not diluted in either CD25+ or CD25− CD4+ cells in the distal lymph nodes of mice receiving either pulsed or unpulsed DCs (Fig. 3). Therefore, DCs are able to induce the proliferation of CD25+ CD4+ T cells from an autoimmune strain in vivo.

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