Expression of FOXP3 mRNA is not confined to CD4+CD25+ T regulatory cells in humans

Morgan, Mary E.; Bilsen, Jolanda van; Bakker, Aleida M.; Heemskerk, Bianca; Schilham, Marco W.; Hartgers, Franca C.; Elferink, B. G.; Zanden, Linda van der; Vries, R. R. P. De; Huizinga, Tom W J; Ottenhoff, Tom H. M.; Toes, René E. M.

doi:10.1016/j.humimm.2004.05.016

Cited by 365 publications

(288 citation statements)

References 21 publications

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“…However, recent studies indicate that Foxp3 is not exclusively expressed in regulatory Tcells [29] and a lack of correlation between the mRNA levels and the actual Foxp3 protein expression has been reported [6,30].…”

Section: Discussionmentioning

confidence: 99%

Impaired regulatory T cell function in germ‐free mice

et al. 2006

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Regulatory T cells (Treg) are crucial for the maintenance of tolerance to auto-antigens and harmless exogenous antigens. Here, we studied the role of the commensal microbiota for the development and function of Treg. CD4 + CD25 + T cells were obtained from peripheral lymph nodes (PLN) and mesenteric lymph nodes (MLN) of germ-free (GF) and conventional (conv) NMRI mice and tested for phenotype and functional suppressive capacity. CD4 + CD25 + T cells from GF mice showed a lower relative gene expression of fork head box p3 gene (Foxp3) and were not as potent suppressors in vitro as CD4 + CD25 + T cells from conv animals. Intracellular staining for Foxp3 and CTLA-4 revealed proportional and regional differences in putative Treg subsets between conv and GF mice. Fewer of the CD4 + CD25 + T cells in GF MLN expressed Foxp3 and CTLA-4, while the expression of these markers was similar amongst the CD4 + CD25 + T cells in PLN of conv and GF mice. The largest difference between conv and GF Treg was observed in the liver draining celiac lymph node, where GF mice had fewer putative Treg as compared to conv mice. We propose that the presence of a microbial flora favors the development of a fully functional Treg population. IntroductionRegulatory T cells down-regulate unwanted and exaggerated immune reactions to auto-antigens as well as innocuous environmental antigens. Different subsets of Treg have been defined. Natural CD4 + CD25 + Treg are positively selected for tissue-specific self-Ag in the thymus and exert their suppressive effect by cell-cell contact-dependent mechanisms [1]. Deficiency in the Treg population or neonatal thymectomy result in multiorgan autoimmune diseases [2][3][4][5][6][7][8]. Treg are characterized by a dense surface expression of CD25 (the a-chain of the IL-2-receptor), glucocorticoidinduced TNF receptor (GITR) and intracellular CTLA-4, however, these markers may be present on activated T cells. CD4 + CD25 + Tregs appear to be unique in transcribing the fork head box p3 gene (Foxp3) transcription factor [6,9], which enable their identification either with PCR are or newly developed mAb to the Foxp3 protein. Lack of a functional Foxp3 gene result in the severe autoimmune syndrome IPEX (immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome), characterized by organ-specific autoimmunity, colitis and high IgE levels [10,11]. Mice with spontaneous or induced mutations in the Foxp3 gene that impair Foxp3 expression fail to develop CD4 + CD25 + Treg and exhibit a syndrome similar to IPEX [5,6].Other subsets of Treg are induced in the periphery and are referred to as Th3 [12][13][14] and Tr1 cells [15][16][17][18][19] can also generate Treg. This implies that the state of the APC and the local cytokine milieu, e.g. in the normal gut where both IL-10 and TGF-b are abundant, can determine the outcome of an immune reaction, and that Treg are induced under these circumstances.The aim of this study was to investigate the phenotype and functionality of CD4 + CD25 + Treg from germ-free (GF) ...

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Section: Discussionmentioning

confidence: 99%

Impaired regulatory T cell function in germ‐free mice

et al. 2006

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“…Heatinactivated parasitic extracts (HIPE) or medium alone were used as "negative" controls while P. falciparum extracts at 10 mg/ml was used as positive control [15]. We chose to quantify the expansion of CD25 high Foxp3 þ Treg populations in cells activated by anti-CD3/CD28 antibodies after 5 days of culture, because at this time the effects of TCR-activation on the expression of Foxp3 gene by CD4 þ T lymphocytes are not evident ( [25,26], our data in Fig. 1C).…”

Section: Effects Of Parasite Extracts On Treg Induction In Resting Ormentioning

confidence: 99%

Effects of soluble extracts from Leishmania infantum promastigotes, Toxoplasma gondii tachyzoites on TGF-β mediated pathways in activated CD4+ T lymphocytes

Clemente

Severini

Castronovo

et al. 2014

Microbes and Infection

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Interference with transforming growth factor-b-mediated pathways helps several parasites to survive for long periods in immunocompetent hosts. Macrophages and dendritic cells infected by Toxoplasma, Leishmania and Plasmodium spp. produce large amounts of transforming growth factor-b and induce the differentiation of antigen-specific T-regulatory cells. Mechanisms not mediated by antigen-presentation could also account for the expansion of T-regulatory cells in parasitic diseases and they also might be mediated through transforming growth factor-breceptor activated pathways. We explored the properties of soluble extracts from Leishmania infantum promastigotes, Toxoplasma gondii tachyzoites, Trichinella spiralis muscle larvae to expand the pool of T-regulatory cells in a population of polyclonally activated T cells in the absence of accessory cells, and compared their effects to those induced by Plasmodium falciparum extracts. Similarly to P. falciparum, L. infantum extracts activate the latent soluble form of transforming growth factor-b and that bound to the membrane of activated T lymphocytes. The interaction of the active cytokine with transforming growth factor-b receptor induces Foxp3 expression by activated lymphocytes, favoring their conversion through the T-regulatory phenotype. Both Toxoplasma gondii and L. infantum extracts are able to induce transforming growth factor-b production by activated T cells in the absence of accessory cells.

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Section: Introductionmentioning

confidence: 99%

“…For instance, while murine Foxp3 is expressed only in Treg, human Foxp3 can also be expressed in conventional human T cells after in vitro culture [8][9][10][11][12]. Human Foxp3 gene was also shown in a number of in vitro cultured, apparently non-suppressive Th1-like human T cell clones [11,12]. Moreover, unlike its murine counterpart, human Foxp3 is usually expressed as two different products, one being the fulllength Foxp3 (Foxp3FL) and the other being an alternatively spliced isoform lacking the exon 2 (Foxp3DE2) [9,13,14].…”

Section: Introductionmentioning

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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Expression of FOXP3 mRNA is not confined to CD4+CD25+ T regulatory cells in humans

Cited by 365 publications

References 21 publications

Impaired regulatory T cell function in germ‐free mice

Impaired regulatory T cell function in germ‐free mice

Effects of soluble extracts from Leishmania infantum promastigotes, Toxoplasma gondii tachyzoites on TGF-β mediated pathways in activated CD4+ T lymphocytes

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

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Expression of FOXP3 mRNA is not confined to CD4+CD25+ T regulatory cells in humans

Cited by 365 publications

References 21 publications

Impaired regulatory T cell function in germ‐free mice

Impaired regulatory T cell function in germ‐free mice

Effects of soluble extracts from Leishmania infantum promastigotes, Toxoplasma gondii tachyzoites on TGF-β mediated pathways in activated CD4+ T lymphocytes

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

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