Regulatory T Cells, Derived from Naïve CD4+CD25− T Cells by In Vitro Foxp3 Gene Transfer, Can Induce Transplantation Tolerance

Chai, Jian-Guo; Xue, Shao-An; Coe, David; Addey, Caroline; Bartók, I; Scott, Diane; Simpson, Elizabeth; Stauss, Hans J.; Hori, Shohei; Sakaguchi, Shimon; Dyson, Julian

doi:10.1097/01.tp.0000159147.56408.9c

Cited by 132 publications

(81 citation statements)

References 26 publications

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“…Importantly, our data demonstrate that when overexpressed, both Foxp3 isoforms are capable of converting conventional CD4 + CD25 -cells into Treg. These latter results confirm and extend the findings of three other studies in the human setting [13,15,16] and of several studies in mice [3,4,[17][18][19][20][21].…”

Section: Discussionsupporting

confidence: 91%

Forced overexpression of either of the two common human Foxp3 isoforms can induce regulatory T cells from CD4⁺CD25^– cells

Aarts-Riemens¹,

Emmelot²,

Verdonck³

et al. 2008

Eur J Immunol

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The forkhead/winged helix transcription factor (Foxp3) is expressed as two different isoforms in humans: the full-length isoform (Foxp3FL) and an alternative-splicing product lacking the exon 2 (Foxp3DE2). We here studied the cellular distribution of Foxp3 isoforms by quantitative PCR and evaluated the functional outcome of retroviral transduction of Foxp3FL and Foxp3DE2 genes into CD4 + CD25 -cells. In PBMC, both isoforms were preferentially expressed in CD4 + CD25 hi cells. In single-cell-sorted and expanded Treg, both Foxp3 isoforms were expressed simultaneously but without a fixed ratio. Forced expression of Foxp3FL or Foxp3DE2 genes in CD4 + CD25 -T cells induced bona fide Treg that not only displayed Treg phenotype but also were anergic and mediated significant suppressive activity against CD3-activated CD4 + CD25 -cells. GFP -nontransduced cells or cells transduced with an empty vector showed no Treg phenotype, anergy or suppressive activities. In conclusion, our results reveal that both Foxp3 isoforms possess similar capacities to induce Treg; however, unnaturally high expression levels are required to convey Treg functions to CD4 + CD25 -cells. As both Foxp3 isoforms appear to be expressed in an independent fashion, studies aiming at quantification of Treg in peripheral blood or in tissue samples can benefit from determination of total Foxp3 levels rather than one of the isoforms.

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Section: Discussionsupporting

confidence: 91%

Forced overexpression of either of the two common human Foxp3 isoforms can induce regulatory T cells from CD4⁺CD25^– cells

Aarts-Riemens¹,

Emmelot²,

Verdonck³

et al. 2008

Eur J Immunol

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“…Foxp3 has important roles not only as a key molecule in the development of regulatory T cells, but also as an inhibitor of T-cell activation and a repressor of transcription factors (31)(32)(33). Regulatory T cells have been widely used in experimental models for treating autoimmune diseases including IBD (13), arthritis (17), diabetes (18,34), and atherosclerosis (35), allergic diseases including asthma (36) and dermatitis (37), and in preventing transplantation rejection (38,39).…”

Section: Discussionmentioning

confidence: 99%

Cell-permeable Foxp3 protein alleviates autoimmune disease associated with inflammatory bowel disease and allergic airway inflammation

Choi

Shin

Sohn

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

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Foxp3 is a key transcription factor for differentiation and function of regulatory T (Treg) cells that is critical for maintaining immunological self-tolerance. Therefore, increasing Treg function by Foxp3 transduction to regulate an inflammatory immune response is an important goal for the treatment of autoimmune and allergic diseases. Here we have generated a cell-permeable Foxp3 protein by fusion with the unique human HHph-1-PTD (protein transduction domain), examined its regulatory function in T cells, and characterized its therapeutic effect in autoimmune and allergic disease models. HHph-1-Foxp3 was rapidly and effectively transduced into cells within 30 min and conferred suppressor function to CD4 + CD25 − T cells as well as directly inhibiting T-cell activation and proliferation. Systemic delivery of HHph-1 Foxp3 remarkably inhibited the autoimmune symptoms of scurfy mice and the development of colitis induced by scurfy or wild-type CD4 T cells. Moreover, intranasal delivery of HHph-1-Foxp3 strongly suppressed ovalbumin-induced allergic airway inflammation. These results demonstrate the clinical potential of the cell-permeable recombinant HHph-1-Foxp3 protein in autoimmune and hypersensitive allergic diseases.

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“…[38][39][40][41] However, the precise definition and an antigen specificity of regulatory cells, as well as the feasibility of obtaining a sufficient number of cells, are notable obstacles for clinical application.…”

Section: Discussionmentioning

confidence: 99%

New differentiation pathway for double-negative regulatory T cells that regulates the magnitude of immune responses

Zhang

Yang

Degauque

et al. 2006

Blood

110

124

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IntroductionIn the peripheral lymphoid tissues of normal mice and humans, 1% to 5% of ␣␤ T-cell receptor-positive (TCR ϩ ) T cells are CD4 Ϫ CD8 Ϫ (double-negative [DN]) T cells. 1,2 MRL/Mpj-lpr/lpr mice have a mutant Fas gene and a massive lymphadenopathy consisting of an age-related accumulation of DN ␣␤TCR ϩ T cells. 3,4 The DN T cells have been shown to possess the capacity to regulate auto-and alloimmune responses and induce immune tolerance. [5][6][7][8] However, the origin of peripheral DN T cells is still unclear. The heterogeneity of DN T-ells in the expression of surface markers suggests that several maturation/differentiation pathways may exist. In murine models, several studies have demonstrated that DN ␣␤ TCR ϩ T cells can be derived directly from CD8 ϩ T cells. [9][10][11][12] Other studies suggest that DN ␣␤ TCR ϩ natural killer T cells (NKT cells) arise extrathymically from bone marrow (BM). 13 More recently, Ford et al reported that DN T regulatory cells can develop outside the thymus, but not from mature CD8 ϩ T-cell precursors. 14 However, a differentiation pathway of peripheral DN T cells from CD4 ϩ T cells was not identified.In this report, we monitored CD4 expression during CD4 ϩ T-cell proliferation and differentiation and identified a new pathway for the generation of a DN regulatory T-cell subset. This pathway uncovered a new intrinsic homeostatic mechanism that regulates the magnitude of immune responses to alloantigen both in vitro and in vivo. Our observations will permit the development of novel, cell-based, therapeutic approaches for the prevention of allograft rejection and for the treatment of autoimmune diseases. Materials and methodsMice Male C57BL/6 (H-2 b ), C57BL/6 congenic for CD45.1, C57BL/6 TEa TCR-transgenic, C57BL/6 perforin gene knock-out (KO), C57BL/6 RAG Ϫ/Ϫ , DBA/2 (H-2 d ), C3H (H-2 k ), and B6D2F1 (H-2 b/d ) mice were obtained from The Jackson Laboratory (Bar Harbor, ME). Foxp3 gfp knock-in C57BL/6 mice were provided by Dr Wenda Gao (Boston, MA). 15 All mice were maintained in the animal facilities of Harvard Institutes of Medicine. Reagents and antibodiesRecombinant mouse interleukin-2 (IL-2), IL-4, and granulocyte-macrophage colony-stimulating factor (GM-CSF) were obtained from Biosource (Camarillo, CA). CD4 ϩ T-cell enrichment column, T-cell enrichment column, and recombinant mouse IL-15 were obtained from R&D Systems (Minneapolis, MN). Fluorochrome-conjugated antibodies to mouse CD3, CD4, CD8, CD25, CD28, CD40, CD44, CD45.1, CD69, CD86, Ter119, B220, CD11b, CD11c, Gr1, NK1.1, TCR␤, TCR␥␦, and isotype controls were obtained from eBioscience (San Diego, CA). Annexin V-PE was purchased from BD Pharmingen (San Diego, CA). CD4 ϩ CD25 ϩ regulatory T cell (Treg) isolation kits, anti-PE microbeads, and magnetic bead separation columns were obtained from Miltenyi Biotec (Auburn, CA). Mitomycin C was obtained from Sigma (St Louis, MO).Purification of CD4 ؉ , CD4 ؉ CD25 ؉ , CD4 ؉ CD25 ؊ , and CD4 ؊ CD8 ؊ DN T cellsSingle-cell suspensions were prepared from the spleens and...

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Regulatory T Cells, Derived from Naïve CD4+CD25− T Cells by In Vitro Foxp3 Gene Transfer, Can Induce Transplantation Tolerance

Abstract: This study provides the first evidence that Foxp3-transduced T cells can control the rejection of an allogeneic transplant and suggests that T-cell Foxp3 gene transfer may have therapeutic value in clinical transplantation.

Cited by 132 publications

References 26 publications

Forced overexpression of either of the two common human Foxp3 isoforms can induce regulatory T cells from CD4⁺CD25^– cells

Forced overexpression of either of the two common human Foxp3 isoforms can induce regulatory T cells from CD4⁺CD25^– cells

Cell-permeable Foxp3 protein alleviates autoimmune disease associated with inflammatory bowel disease and allergic airway inflammation

New differentiation pathway for double-negative regulatory T cells that regulates the magnitude of immune responses

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Regulatory T Cells, Derived from Naïve CD4+CD25− T Cells by In Vitro Foxp3 Gene Transfer, Can Induce Transplantation Tolerance

Abstract: This study provides the first evidence that Foxp3-transduced T cells can control the rejection of an allogeneic transplant and suggests that T-cell Foxp3 gene transfer may have therapeutic value in clinical transplantation.

Cited by 132 publications

References 26 publications

Forced overexpression of either of the two common human Foxp3 isoforms can induce regulatory T cells from CD4+CD25– cells

Forced overexpression of either of the two common human Foxp3 isoforms can induce regulatory T cells from CD4+CD25– cells

Cell-permeable Foxp3 protein alleviates autoimmune disease associated with inflammatory bowel disease and allergic airway inflammation

New differentiation pathway for double-negative regulatory T cells that regulates the magnitude of immune responses

Contact Info

Product

Resources

About

Forced overexpression of either of the two common human Foxp3 isoforms can induce regulatory T cells from CD4⁺CD25^– cells

Forced overexpression of either of the two common human Foxp3 isoforms can induce regulatory T cells from CD4⁺CD25^– cells