Regulatory T cells were initially identified and isolated in the mouse, by virtue of their endogenous expression of CD25 (IL-2R alphachain) and shown to inhibit both the in vivo development of autoimmunity and the in vitro proliferation of nonregulatory, CD4+CD25- T cells. In contrast to mouse cells, human regulatory T cells are not purified by isolating all CD25-expressing CD4 T cells ex vivo. Such cells can be isolated by targeting only the small percentage of human CD4 T cells that express high levels of CD25. This is best achieved by FACS sorting using the level of CD25 expressed on CD4- T cells to place the gate for discriminating high expression of CD25. This unit provides two widely used methods to isolate (FACS) or to enrich (magnetic beads) human CD4+CD25+ regulatory T cells from blood, along with an in vitro coculture assay to measure the anergic and suppressive features of human CD4+CD25+ regulatory T cells.
[Show abstract][Hide abstract] ABSTRACT: Compared with conventional drug therapy, autologous hemopoietic stem cell transplantation (HSCT) can induce very-long-term remission in refractory lupus patients. Herein, we show that in posttransplant patients, both CD4(+)CD25(high)FoxP3(+) and an unusual CD8(+)FoxP3(+) Treg subset return to levels seen in normal subjects; accompanied by almost complete inhibition of pathogenic T cell response to critical peptide autoepitopes from histones in nucleosomes, the major lupus autoantigen from apoptotic cells. In addition to a stably sustained elevation of FoxP3, posttransplant CD8 T cells also maintained markedly higher expression levels of latency-associated peptide (LAP), CD103, PD-1, PD-L1, and CTLA-4, as compared with pretransplant CD8 T cells that were identically treated by a one-time activation and rest in short-term culture. The posttransplant CD8 regulatory T cells (Treg) have autoantigen-specific and nonspecific suppressive activity, which is contact independent and predominantly TGF-beta dependent. By contrast, the pretransplant CD8 T cells have helper activity, which is cell contact dependent. Although CD4(+)CD25(high) Treg cells return during clinical remission of conventional drug-treated lupus, the posttransplant patient's CD8 Treg cells are considerably more potent, and they are absent in drug-treated patients in whom CD4 T cell autoreactivity to nucleosomal epitopes persists even during clinical remission. Therefore, unlike conventional drug therapy, hemopoietic stem cell transplantation generates a newly differentiated population of LAP(high)CD103(high) CD8(TGF-beta) Treg cells, which repairs the Treg deficiency in human lupus to maintain patients in true immunological remission.
The Journal of Immunology 11/2009; 183(10):6346-58. DOI:10.4049/jimmunol.0901773 · 4.92 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Interleukin-2 (IL-2) is one of the most studied cytokines driving T-cell proliferation, activation and survival. It binds to the IL-2 receptor consisting of three chains, the α (CD25), β and common γ (γc). The binding of the CD25 chain to IL-2 is necessary to expose high-affinity binding sites for the β and γc chains, which, in turn, are responsible for downstream signalling. A high level of soluble CD25 (sCD25) has been associated with a poor prognosis in patients with non-Hodgkin's lymphoma. The function and source of origin of this soluble receptor is not well investigated. In the present study we hypothesized that T regulatory (Treg) cells may release CD25 to act as a decoy receptor for IL-2, thereby depriving T-effector cells of IL-2. Peripheral blood from patients with B-cell malignancies (n = 26) and healthy controls (n = 27) was investigated for the presence and function of FoxP3(+) Treg cells and sCD25 by multi-colour flow cytometry and enzyme-linked immunosorbent assay. Further, the proliferative capacity of T cells was evaluated with or without the presence of recombinant sCD25. The results demonstrate that Treg cells from patients had lower CD25 expression intensity and that they released CD25 in vitro. Further, high levels of Treg cells correlated with sCD25 plasma concentration. Recombinant sCD25 could suppress T-cell proliferation in vitro. In conclusion, the release of sCD25 by Treg cells may be a mechanism to deprive IL-2 and thereby inhibit anti-tumour T-cell responses.
[Show abstract][Hide abstract] ABSTRACT: Dendritic cells (DC) are professional antigen-presenting cells defined by their ability to transport incoming infectious signals from the periphery to T cell areas in lymphoid organs and by their unique properties to induce primary T cell activation. As sentinels of immunity DC play a critical role in the initiation of immune responses. Thus, they are key targets in antigen-specific immunotherapeutic strategies for cancer. However, beside this essential immunostimulatory function in the immune system, DC also play an important role in the maintenance of peripheral tolerance. Dependent on subtype and mode of activation, tissue resident immature DC differentiate into immunostimulatory or immunosuppressive antigen-presenting cells with a strong capacity to activate or to inhibit T cell responses, respectively. This review summarizes our current knowledge about the complex interaction between DC and T cells considering both--immunity and tolerance--as well as the possibilities to use this knowledge for development of novel diagnostic and immunotherapeutic strategies to treat immune-imbalanced human diseases such as cancer, allergy, and autoimmunity.
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