Naturally anergic and suppressive CD25+CD4+ T cells as a functionally and phenotypically distinct immunoregulatory T cell subpopulation

Kuniyasu, Yuhshi; Takahashi, Takeshi; Itoh, Masae; Shimizu, Jun; Toda, Gotaroh; Sakaguchi, Shimon

doi:10.1093/intimm/12.8.1145

Cited by 264 publications

(220 citation statements)

References 43 publications

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“…Despite the functional significance of CD25 and IL-2 signalling in naturally occurring Treg [11][12][13][14][15][16], the data presented here document deletion of diabetogenic cells by the fusion protein. Targeting cells that express the IL-2 receptor decreased the responsiveness to alloantigens in vitro, impaired adoptive transfer of the disease into NOD SCID mice and antagonised cyclophosphamide-induced destructive insulitis.…”

Section: Discussionmentioning

confidence: 63%

“…Third, FOXP3 + T cells in the pancreas and draining lymphatics are less sensitive to apoptosis induced by IL2-cas, resulting in expansion of C25 − FOXP3 + cells. Increased fractional expression of FOXP3 in the thymus, the origin of naturally occurring Treg [11,12] might be beneficial to restoration and maintenance of self-tolerance through resetting of the regulatory/effector equilibrium.…”

Section: Discussionmentioning

confidence: 99%

“…IL-2 is an attractive target of immunotherapy as an important constituent of immune activation [9,10]. Subsets of naturally occurring Treg that emerge from the thymus as a distinct cell type [11,12] are not only characterised by expression of high levels of the high-affinity α chain of the IL-2 receptor (CD25) [13], but also depend on IL-2 for their expansion and function [14,15]. The implications and pleiotropic functions of IL-2 in autoimmune disorders have been extensively debated.…”

Section: Introductionmentioning

confidence: 99%

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Targeting of IL-2 receptor with a caspase fusion protein disrupts autoimmunity in prediabetic and diabetic NOD mice

Yarkoni¹,

Kaminitz

Sagiv³

et al. 2009

Diabetologia

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Aims/hypothesis Interruption of IL-2 signalling is an attractive therapeutic target in autoimmune disorders. In this study we evaluated the effect of a fusion protein composed of IL-2 and caspase-3 (IL2-cas) on NOD mice, as compared with disease induction by cyclophosphamide. Methods IL2-cas was assessed in NOD mice at various ages and in conjunction with cyclophosphamide administration. The effect of IL2-cas on diabetogenic cells was evaluated in adoptive transfer experiments and in cell suspension in vitro. Results IL2-cas induced apoptosis in T cells expressing the α chain of the IL-2 receptor (cluster of differentiation [CD] 25) in vitro, with superior survival of T cells expressing CD4 and forkhead box P3 (FOXP3). The fusion protein decreased mixed lymphocyte reactivity, and pretreatment with IL2-cas decreased the efficacy of adoptive transfer of diabetes into NOD severe combined immunodeficiency mice. Administration of one dose of IL2-cas decreased the incidence of diabetes in NOD mice, showing a superior beneficial effect when administered at young age, and effectively blocked induction of hyperglycaemia by cyclophosphamide, reducing the severity of islet inflammation. Administration of IL2-cas caused an acute increase in CD25 -FOXP3 + T cells in the lymph nodes, pancreas and thymus in NOD mice, with similar effects in wild-type mice. Administration of IL2-cas after onset of hyperglycaemia resulted in superior survival. Conclusions/interpretation Targeted elimination of cells expressing the IL-2 receptor by this fusion protein disrupts the autoimmune pathogenesis in prediabetic and diabetic NOD mice, despite depletion of CD25 + regulatory T cells. Furthermore, this particular fusion protein is permissive to the development of FOXP3 + T cells that might contribute to protracted protection from the progression of insulitis and overt hyperglycaemia.

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Section: Discussionmentioning

confidence: 63%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Targeting of IL-2 receptor with a caspase fusion protein disrupts autoimmunity in prediabetic and diabetic NOD mice

Yarkoni¹,

Kaminitz

Sagiv³

et al. 2009

Diabetologia

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“…T reg cells must be stimulated to exert their suppressive effects; however, once stimulated, T reg cells act in an Ag-nonspecific manner (8,9,18,19). In vitro, the suppressive abilities of the T reg cells are connected to the anergic state, because addition of IL-2 not only breaks the anergy of the T reg cells but also abrogates their ability to suppress proliferation (20).…”

Section: Deficiency Of the Src Homology Region 2 Domain-containing Phmentioning

confidence: 99%

“…These assays were performed as described previously (20,35). Briefly, to assess proliferation, 2.5 ϫ 10 4 CD4 ϩ CD25 Ϫ or CD4 ϩ CD25 ϩ T cells (electronically sorted to a purity of Ͼ95% as described above) were plated in triplicate in 200 l of RPMI 1640 medium (supplemented with 10% FCS, 5 ϫ 10 Ϫ5 M 2-ME, 2 mM L-glutamine, and antibiotics) in 96-well plates.…”

Section: Proliferation and Suppression Assaysmentioning

confidence: 99%

Deficiency of the Src Homology Region 2 Domain-Containing Phosphatase 1 (SHP-1) Causes Enrichment of CD4+CD25+ Regulatory T Cells

Carter

Calabrese

Lorenz

2005

The Journal of Immunology

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A subpopulation of T cells, named regulatory T cells (Treg cells), has been shown to play a key role in tolerance and the prevention of autoimmunity. It is not known how changes in TCR signal strength during thymic T cell development affect the generation of a Treg population. In this study, we took two different strategies to modulate the TCR signal strength: an intrinsic approach, where signaling was enhanced by the loss of a negative regulator, and an extrinsic approach, where signaling strength was altered through variations in the concentrations of the selecting peptide. The tyrosine phosphatase Src homology region 2 domain-containing phosphatase 1 (SHP-1) is a known negative regulator of TCR-mediated signaling. motheaten mice, lacking expression of SHP-1, showed a 2- to 3-fold increase in the percentage of CD4+CD25+ Treg cells within the CD4+ T cells. Similarly, the percentage of Treg cells was heightened in fetal thymic organ cultures (FTOCs) derived from motheaten mice compared with wild-type FTOCs, thus establishing the thymic origin of these Treg cells. Using FTOCs derived from DO11.10 TCR transgenic mice, we demonstrated that exposure to increasing concentrations of the cognate OVA peptide favored the appearance of Treg cells. Our data suggest that the development of CD4+CD25+ Treg cells is intrinsically different from non-Treg cells and that Treg cells are selectively enriched under conditions of enhanced negative selection. Our data also reveal a key role for the SHP-1-mediated regulation of TCR signal strength in influencing the ratio of Treg vs non-Treg cells.

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CD4+CD25+ T cells as immunoregulatory T cells in vitro

et al. 2002

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We have further characterized the in vitro phenotype and function of anergic and suppressive CD4+25+ T cells. Following TCR ligation, DO.11.10 CD4+25+ T cells suppress the activation of OT‐1 CD8+25– T cells in an antigen nonspecific manner. Although suppression was seen when using a mixture of APC from both parental strains, it was very much more marked when using F1 APC. APC pretreated with, and then separated from CD4+25+ T cells did not have diminished T cell costimulatory function, suggesting that APC are not the direct targets of CD4+25+ T cell regulation. CTLA‐4 blockade failed to abrogate suppression by CD4+25+ T cells in mixing experiments. Although CD4+25+ T cells failed to respond following cross‐linking of TCR, they could be induced to proliferate following the addition of exogenous IL‐2, allowing the generation of a T cell line from CD4+25+ T cells. After the first in vitro restimulation, CD4+25+ T cells were still anergic and suppressive following TCR engagement. However, after three rounds of restimulation, their anergic and suppressive status was abrogated.

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Naturally anergic and suppressive CD25+CD4+ T cells as a functionally and phenotypically distinct immunoregulatory T cell subpopulation

Cited by 264 publications

References 43 publications

Targeting of IL-2 receptor with a caspase fusion protein disrupts autoimmunity in prediabetic and diabetic NOD mice

Targeting of IL-2 receptor with a caspase fusion protein disrupts autoimmunity in prediabetic and diabetic NOD mice

Deficiency of the Src Homology Region 2 Domain-Containing Phosphatase 1 (SHP-1) Causes Enrichment of CD4+CD25+ Regulatory T Cells

CD4+CD25+ T cells as immunoregulatory T cells in vitro

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