Inducing and expanding regulatory T cell populations by foreign antigen

Kretschmer, Karsten; Apostolou, Irina; Hawiger, Daniel; Khazaie, Khashayarsha; Nussenzweig, Michel C.; Boehmer, Harald von

doi:10.1038/ni1265

Cited by 1,140 publications

(1,151 citation statements)

References 31 publications

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“…The upregulation of surface expression of galectin-3 is particularly interesting given the recent observation that galectin-3, recruited intracellularly to the immunological synapse, negatively regulates TCR-mediated CD4 1 T-cell activation [28]. Generation of Treg has been associated with suboptimal T-cell activation, resulting from antigen presentation by immature or sub-optimally primed DC [29,30]. The ability of galectin-3 to influence the immunological synapse together with the ability of SEA to modulate DC maturation may play a key role in favoring the development of Foxp3-expressing cells in our T-cell/DC co-cultures [25].…”

Section: Discussionmentioning

confidence: 99%

Importance of TLR2 in the direct response of T lymphocytes to Schistosoma mansoni antigens

et al. 2010

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The immunomodulatory effect of Schistosoma mansoni antigens has often been attributed to interaction with PRR expressed on APC. Our previous work has shown that S. mansonisoluble egg antigen (SEA) can induce, together with a Th2 response, TGF-b-dependent Foxp3 expression in naïve CD4 1 T cells from NOD mice. We found that SEA can directly upregulate the expression of surface-bound TGF-b in purified CD4 1 T cells in the absence of accessory cell interactions. In this study, we show that the C-type lectin receptors DEC-205 and galectin-3 were involved in the direct interaction between S. mansoni antigens and CD4 1 T cells. SEA was able to enhance CD4 1 T-cell secretion of bioactive TGF-b in response to TLR2 ligand stimulation, in the absence of APC. We also show that TLR2 expressed on CD4 1 T cells was important for the Foxp3 expression induced by SEA.

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Section: Discussionmentioning

confidence: 99%

Importance of TLR2 in the direct response of T lymphocytes to Schistosoma mansoni antigens

et al. 2010

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“…However, induction or forced expression of Foxp3 has been shown to confer immunosuppressive capacity to Tcon (21,22). In addition, specific treatments such as the delivery of antigens to immature DCs can induce conversion of some Tcon into Foxp3-expressing cells with an immunosuppressive function (42). Therefore, quantification of Foxp3-expressing T cells should reflect the actual Treg pool that includes both natural and peripherally converted Treg.…”

Section: Discussionmentioning

confidence: 99%

Low number of regulatory T cells in skin lesions of patients with cutaneous lupus erythematosus

Franz¹,

Fritzsching²,

Riehl³

et al. 2007

Arthritis & Rheumatism

123

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Objective. To define the phenotype and function of CD4؉,CD25؉ regulatory T cells (Treg) in patients with cutaneous lupus erythematosus (CLE), a heterogeneous autoimmune disease characterized primarily by inflammatory skin lesions.Methods. The number of Treg in skin specimens obtained from patients with various subtypes of CLE was investigated by immunohistochemical analysis, using anti-Foxp3 and anti-CD4 monoclonal antibodies. Furthermore, characterization of peripheral blood CD4؉,CD25؉ Treg from normal healthy donors and patients with CLE was carried out by flow cytometry, analyzing the expression of Foxp3 and Treg subpopulations. We also purified CD4؉,CD25 high Treg obtained from patients with CLE and tested the sensitivity of these cells to CD95L-mediated apoptosis.Results. Quantitative analysis of CD4؉ T cells in skin lesions from patients with CLE revealed that the number was similar to that in lesions from patients with other chronic inflammatory diseases, but the number of Foxp3؉ Treg in CLE was significantly reduced. There was no correlation between disease subtype and the frequency of Foxp3؉ Treg in the skin of patients with CLE. In peripheral blood, no significant differences were observed in the number and phenotype of CD4؉,CD25؉ Treg or in the sensitivity to apoptosis of CD4؉,CD25 high Treg derived from patients with CLE and those derived from normal healthy donors.Conclusion. These data suggest that an organspecific abnormality of Treg in the skin underscores the importance of analyzing Treg in the affected tissue. Such a local process might give insight into the pathogenic mechanisms of CLE and differs from a global peripheral dysfunction as reported for patients with a systemic manifestation of the disease.

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“…However, it is now appreciated that Tregs can be generated not only in the thymus but also in the periphery, and even in vitro from naive CD4 + T cells. Thus, Treg populations can be divided into two groups (4)-namely, thymus-derived Tregs (tTregs) and those that are derived outside the thymus, known as induced Tregs, which can be further classified into two subgroups: Tregs generated in vivo (referred to as peripheral Tregs [pTregs]) (5)(6)(7)(8) and Tregs generated in vitro by TGF-b (referred to as iTregs hereafter) (9). Although all three Treg populations show suppressive activity (10,11) and sometimes can be interchangeable in vivo (12), each type of Treg shows unique genetic (13) and epigenetic (14) profiles, which suggests that each type develops under different environments.…”

Section: Vitamin C Facilitates Demethylation Of the Foxp3 Enhancer Inmentioning

confidence: 99%

Vitamin C Facilitates Demethylation of the Foxp3 Enhancer in a Tet-Dependent Manner

Nair

Song

2016

The Journal of Immunology

147

100

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Demethylation of CpG motifs in the Foxp3 intronic element, conserved noncoding sequence 2 (CNS2), is indispensable for the stable expression of Foxp3 in regulatory T cells (Tregs). In this study, we found that vitamin C induces CNS2 demethylation in Tregs in a ten-eleven-translocation 2 (Tet2)-dependent manner. The CpG motifs of CNS2 in Tregs generated in vitro by TGF-β (iTregs), which were methylated originally, became demethylated after vitamin C treatment. The conversion of 5-methylcytosin into 5-hydroxymethylcytosin was more efficient, and the methyl group from the CpG motifs of Foxp3 CNS2 was erased rapidly in iTregs treated with vitamin C. The effect of vitamin C disappeared in Tet2−/− iTregs. Furthermore, CNS2 in peripheral Tregs in vivo, which were demethylated originally, became methylated after treatment with a sodium-dependent vitamin C transporter inhibitor, sulfinpyrazone. Finally, CNS2 demethylation in thymic Tregs was also impaired in Tet2−/− mice, but not in wild type mice, when they were treated with sulfinpyrazone. Collectively, vitamin C was required for the CNS2 demethylation mediated by Tet proteins, which was essential for Foxp3 expression. Our findings indicate that environmental factors, such as nutrients, could bring about changes in immune homeostasis through epigenetic mechanisms.

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Inducing and expanding regulatory T cell populations by foreign antigen

Cited by 1,140 publications

References 31 publications

Importance of TLR2 in the direct response of T lymphocytes to Schistosoma mansoni antigens

Importance of TLR2 in the direct response of T lymphocytes to Schistosoma mansoni antigens

Low number of regulatory T cells in skin lesions of patients with cutaneous lupus erythematosus

Vitamin C Facilitates Demethylation of the Foxp3 Enhancer in a Tet-Dependent Manner

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