FOXP3 Identifies Regulatory CD25<sup>bright</sup>CD4<sup>+</sup> T Cells in Rheumatic Joints

Cao, Duojia; Börjesson, Ola; Larsson, Patrik; Rudin, Anna; Gunnarsson, Iva; Klareskog, Lars; Malmström, Vivianne; Trollmo, Christina

doi:10.1111/j.1365-3083.2006.001755.x

Cited by 65 publications

(49 citation statements)

References 20 publications

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“…FOXP3 expression is known to be increased upon activation of human T cells [56][57][58]. However, the increased numbers of CD4 1 FOXP3 1 T cells found in autoimmune inflammatory environments such as EAE or the rheumatoid joint [59][60][61] has been used to support the argument that Treg are expanded in inflammation but are unable to establish control [62]. Although defective CTLA-4 function and an expanded CD4 1 FOXP3 1 population in lupus patients may not be connected, there is a striking parallel found in CTLA-4-deficient mice [1,2].…”

Section: Discussionmentioning

confidence: 99%

Abnormal CTLA‐4 function in T cells from patients with systemic lupus erythematosus

et al. 2010

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CTLA‐4 is a critical gatekeeper of T‐cell activation and immunological tolerance and has been implicated in patients with a variety of autoimmune diseases through genetic association. Since T cells from patients with the autoimmune disease systemic lupus erythematosus (SLE) display a characteristic hyperactive phenotype, we investigated the function of CTLA‐4 in SLE. Our results reveal increased CTLA‐4 expression in FOXP3− responder T cells from patients with SLE compared with other autoimmune rheumatic diseases and healthy controls. However, CTLA‐4 was unable to regulate T‐cell proliferation, lipid microdomain formation and phosphorylation of TCR‐ζ following CD3/CD28 co‐stimulation, in contrast to healthy T cells. Although lupus T cells responded in vitro to CD3/CD28 co‐stimulation, there was no parallel increase in CTLA‐4 expression, which would normally provide a break on T‐cell proliferation. These defects were associated with exclusion of CTLA‐4 from lipid microdomains providing an anatomical basis for its loss of function. Collectively our data identify CTLA‐4 dysfunction as a potential cause for abnormal T‐cell activation in patients with SLE, which could be targeted for therapy.

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Section: Discussionmentioning

confidence: 99%

Abnormal CTLA‐4 function in T cells from patients with systemic lupus erythematosus

et al. 2010

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“…Since both Foxp3 isoforms appear to possess similar functions but their mRNA expression levels show no fixed ratio at the PBMC level, it seems important to determine total Foxp3 mRNA levels rather than quantifying the mRNA of only one of the isoforms. Fortunately, until now several studies have used PCR primer sets that amplify both Foxp3FL and Foxp3DE2 isoforms [25][26][27][28][29][30]. Nonetheless, interpretation of several other studies may be difficult since either the amplified Foxp3 region was not exactly reported [31][32][33][34] or only the full-length Foxp3 mRNA was amplified without any reasoning [35].…”

Section: Discussionmentioning

confidence: 99%

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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“…Unfortunately, immunohistochemical analysis for the presence of Treg in inflamed tissue of patients with autoimmune diseases has been performed in very few studies. To our knowledge, Treg have been visualized only in the synovial fluid and synovial membrane of patients with rheumatoid arthritis (13,36) and in the lymph nodes of patients with active SLE (16) or sarcoidosis (37).…”

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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FOXP3 Identifies Regulatory CD25^brightCD4⁺ T Cells in Rheumatic Joints

Cited by 65 publications

References 20 publications

Abnormal CTLA‐4 function in T cells from patients with systemic lupus erythematosus

Abnormal CTLA‐4 function in T cells from patients with systemic lupus erythematosus

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

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

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FOXP3 Identifies Regulatory CD25brightCD4+ T Cells in Rheumatic Joints

Cited by 65 publications

References 20 publications

Abnormal CTLA‐4 function in T cells from patients with systemic lupus erythematosus

Abnormal CTLA‐4 function in T cells from patients with systemic lupus erythematosus

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

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

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FOXP3 Identifies Regulatory CD25^brightCD4⁺ T Cells in Rheumatic Joints

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