Regulatory T Cells and Organ Transplantation

Sir William Dunn School of Pathology, South Parks Road, Oxford OX13RE, UK.
Seminars in Immunology (Impact Factor: 5.17). 05/2004; 16(2):119-26. DOI: 10.1016/j.smim.2003.12.007
Source: PubMed


Empirical studies attempting to explain tolerance to transplanted tissues have demonstrated a regulatory role for CD4+ T-cells. We here propose that regulatory T-cells mediating transplantion tolerance comprise two sets which can functionally complement each other. The CD4+CD25+ "natural regulator" arises in the thymus, and is preoccupied with self-antigens expressed at sites of inflammation. The second, comprising both CD4+CD25+ (FoxP3+) and CD4+CD25- Tr1-like cells are induced by persistent danger-free antigen in the periphery. The role of these cells is to moderate immune responses to prevent tissue destruction while allowing microbial elimination.

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    • "CD4+CD25+ regulatory T cells (Tregs) were claimed to be important players in the tolerance towards the fetus bearing alloantigens [11], [12], [13]. Diminished number of Tregs was associated with immunological rejection of fetus, which could be prevented by adoptively transferring Tregs from normal pregnant mice into abortion-prone animals [14], [15]. "
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    ABSTRACT: Toxoplasma gondii is an opportunistic intracellular parasite that is highly prevalent in human and warm-blooded animals throughout the world, leading to potentially severe congenital infections. Although the abortion caused by T. gondii is believed to be dependent on the timing of maternal infection during pregnancy, the mechanism remains unclear. This study was focused on the effects of T. gondii excreted-secreted antigens on pregnant outcomes and CD4(+)CD25(+) Foxp3(+) regulatory T cells at different stages of pregnancy. The results showed that in mice the frequency and suppressive function of CD4(+)CD25(+) regulatory cells were diminished after injection of T. gondii excreted-secreted antigens at early and intermediate stages of pregnancy. The abortion caused by T. gondii excreted-secreted antigens at early pregnancy could be partly prevented by adoptively transferring of CD4(+)CD25(+) cells from the mice injected with T. gondii excreted-secreted antigens at late pregnancy, but not from the mice with the same treatment at early pregnancy. Furthermore, T. gondii excreted-secreted antigens induced apoptosis of CD4(+)CD25(+) regulatory cells of mice in early and intermediate stages of pregnancy by down-regulating their Bcl-2 expressions and Bcl-2/Bax ratio. This study provides new insights into the mechanism that T. gondii infection is the high risk factor for abortion in early pregnancy.
    PLoS ONE 07/2013; 8(7):e69012. DOI:10.1371/journal.pone.0069012 · 3.23 Impact Factor
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    • "CD8 + CD28 T S and T reg cells share expression of molecular markers, especially FOXP3 [30]. T S cells have shown antigenspecific immunoregulatory activities in vitro [31] [32] [33] and in vivo in human transplant recipients [34] [35], in human cancer [36], and in murine autoimmune diseases [37]. The induction of transplantation tolerance by T S cells is mediated by mechanisms different from those mediated by CD4 + CD25 + T reg cells [38]. "
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    ABSTRACT: Preventing or curing an immune-mediated disease requires functional immune cells, in particular T cells, including helper (CD4+; Th) and cytotoxic (CD8+; Tc) T cells. Based on the type of the antigen presenting cells, the nature of antigens, and the cytokine milieu, CD4+ T cells exhibit high plasticity to differentiate into different subsets with stimulatory or regulatory functions. For instance, Th cells can differentiate into Th1 and Th2 type cells, which produce inflammatory (IL-2, IFN-γ, TNF-α, IL-12) and anti-inflammatory (IL-4, IL-10, and TGF-ß) cytokines, respectively. Th cells can also differentiate into a third type of Th cells designated as Th17 type cell that produces IL-17 and mimics the effects of Th1 cells. Similar to Th cells, Tc can differentiate into Tc1, Tc2, and Tc17 subsets that produce cytokine profiles similar to those produced by Th1, Th2, and Th17 cells, respectively. Under certain condition, Th type cells can also differentiate into a regulatory (Treg) type cell, which produces immunosuppressive cytokines such as TGF-ß and IL-10. Similarly, Th17 and Tc1 type cells can acquire immunoreglatory properties. This article sheds a light on how this T cell plasticity shapes the nature of the immune cell responses to inflammation, infection, and cancer.
    Immunology Endocrine & Metabolic Agents - Medicinal Chemistry (Formerly Current Medicinal Chemistry - Immunology Endocrine & Metabolic Agents) 05/2009; 9(2):90-105. DOI:10.2174/187152209789000687
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    • "It might also be that gp96 influences the presence or activities, or both, of the naturally occurring CD4 ϩ CD25 ϩ immunoregulatory T-cell subset (Shevach 2002; Gavin and Rudensky 2003; Wood and Sakaguchi 2003; Lee et al 2004; Waldmann et al 2004), especially given that these cells express Toll-like receptors (TLRs; Caramalho et al 2003; Zanin-Zhorov et al 2006) for which gp96 is a reported ligand (Vabulas et al 2002a, 2002b; Binder et al 2004). It is certainly known that the ligation of TLRs on naturally occurring CD4 ϩ CD25 ϩ T cells by LPS (Caramalho et al 2003) or the stress protein Hsp60, which is also a reported ligand for TLRs (Ohashi et al 2000; Vabulas et al 2001; Zanin-Zhorov et al 2003, 2006; Cohen-Sfady et al 2005), can enhance the regulatory function of CD4 ϩ CD25 ϩ T cells (Caramalho et al 2003; Zanin-Zhorov et al 2006). "
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    ABSTRACT: High-dose gp96 has been shown to inhibit experimental autoimmune disease by a mechanism that appears to involve immunoregulatory CD4+ T cells. This study tested the hypothesis that high-dose gp96 administration modifies allograft rejection and associated inflammatory events. Wistar cardiac allografts were transplanted into Lewis recipient rats and graft function was monitored daily by palpation. Intradermal administration of gp96 purified from Wistar rat livers (100 microg) at the time of transplantation and 3 days later significantly prolonged allograft survival (14 vs 8 days in phosphate-buffered saline [PBS]-treated recipients; P = 0.009). Rejected allografts from gp96-treated animals were significantly less enlarged than allografts from their PBS-treated counterparts (2.8 vs 4.3 g; P < 0.004). Gp96 was also effective when administered on days 1 and 8 (13 vs 7 days), but not if it was derived from recipient (Lewis) liver tissue or administered on days 0, 3, and 6. In parallel studies, CD3+ T cells from gp96-treated untransplanted animals secreted less interleukin (IL)-4, IL-10, and interferon (IFN)-gamma after in vitro polyclonal stimulation than CD3+ T cells from PBS-treated animals. Gp96 administration might therefore influence the induction of immunity to coencountered antigenic challenges and inflammatory events by inducing what appears to be a state of peripheral T-cell hyporesponsiveness.
    Cell Stress and Chaperones 03/2007; 12(1):71-82. DOI:10.1379/CSC-237R.1 · 3.16 Impact Factor
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