Human CD4+CD25+ regulatory T cells: proteome analysis identifies galectin-10 as a novel marker essential for their anergy and suppressive function

Kubach, Jan; Lutter, Petra; Bopp, Tobias; Stoll, Sabine; Becker, Christian; Hüter, Eva; Richter, Christoph; Weingarten, Petra; Warger, Tobias; Knop, Jürgen; Müllner, Stefan; Wijdenes, John; Schild, Hansjörg; Schmitt, Edgar; Jonuleit, Helmut

doi:10.1182/blood-2007-01-069229

Cited by 183 publications

(194 citation statements)

References 35 publications

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“…In particular, not only high expression of the IL-2R a-chain (CD25) but also CTLA-4, GITR, and intracellular expression of Galectin-10 have been associated with Treg phenotype and function. 42,43 As shown previously 26,37 and confirmed here, SeAx cells express high levels of CD25 (Figure 7c). CTLA-4, which has a critical function in cell-mediated suppression, 44 was detected at the mRNA level (Figure 7a) and by intracellular staining (Figure 7d), but no significant surface expression could be detected even after treatment with phorbol ester and ionomycin (data not shown).…”

Section: Malignant T Cells Display Surface Expression Of Cd25 But Notsupporting

confidence: 55%

Malignant Tregs express low molecular splice forms of FOXP3 in Sézary syndrome

et al. 2008

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Sé zary syndrome (SS) is an aggressive variant of cutaneous T-cell lymphoma. During disease progression, immunodeficiency develops; however, the underlying molecular and cellular mechanisms are not fully understood. Here, we study the regulatory T cell (Treg) function and the expression of FOXP3 in SS. We demonstrate that malignant T cells in 8 of 15 patients stain positive with an anti-FOXP3 antibody. Western blotting analysis shows expression of two low molecular splice forms of FOXP3, but not of wild-type (wt) FOXP3. The malignant T cells produce interleukin-10 and TGF-b and suppress the growth of non-malignant T cells. The Treg phenotype and the production of suppressive cytokines are driven by aberrant activation of Jak3 independent of the FOXP3 splice forms. In contrast to wt FOXP3, the low molecular splice forms of FOXP3 have no inhibitory effect on nuclear factor-jB (NF-jB) activity in reporter assays which is in keeping with a constitutive NF-jB activity in the malignant T cells. In conclusion, we show that the malignant T cells express low molecular splice forms of FOXP3 and function as Tregs. Furthermore, we provide evidence that FOXP3 splice forms are functionally different from wt FOXP3 and not involved in the execution of the suppressive function. Thus, this is the first description of FOXP3 splice forms in human disease.

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Section: Malignant T Cells Display Surface Expression Of Cd25 But Notsupporting

confidence: 55%

Malignant Tregs express low molecular splice forms of FOXP3 in Sézary syndrome

et al. 2008

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“…4A). The strong staining for Galactin-10 verified the identity of human nTreg (29). In Tconv NFAT proteins were both cytoplasmic and nuclear, where stimulation promoted expression and nuclear transportation.…”

Section: Resultsmentioning

confidence: 94%

“…Human T-cell subsets (29,51) and murine CD4 + CD25 + nTreg and CD4 + CD25 − Tconv (26) were isolated and stimulated as before. Details can be found in SI Materials and Methods.…”

Section: Methodsmentioning

confidence: 99%

Dependence on nuclear factor of activated T-cells (NFAT) levels discriminates conventional T cells from Foxp3 ⁺ regulatory T cells

Vaeth

Schliesser

Müller

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Several lines of evidence suggest nuclear factor of activated T-cells (NFAT) to control regulatory T cells: thymus-derived naturally occurring regulatory T cells (nTreg) depend on calcium signals, the Foxp3 gene harbors several NFAT binding sites, and the Foxp3 (Fork head box P3) protein interacts with NFAT. Therefore, we investigated the impact of NFAT on Foxp3 expression. Indeed, the generation of peripherally induced Treg (iTreg) by TGF-β was highly dependent on NFAT expression because the ability of CD4 + T cells to differentiate into iTreg diminished markedly with the number of NFAT family members missing. It can be concluded that the expression of Foxp3 in TGF-β-induced iTreg depends on the threshold value of NFAT rather than on an individual member present. This is specific for iTreg development, because frequency of nTreg remained unaltered in mice lacking NFAT1, NFAT2, or NFAT4 alone or in combination. Different from expectation, however, the function of both nTreg and iTreg was independent on robust NFAT levels, reflected by less nuclear NFAT in nTreg and iTreg. Accordingly, absence of one or two NFAT members did not alter suppressor activity in vitro or during colitis and transplantation in vivo. This scenario emphasizes an inhibition of high NFAT activity as treatment for autoimmune diseases and in transplantation, selectively targeting the proinflammatory conventional T cells, while keeping Treg functional.gene regulation | tolerance | autoimmunity

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“…We found that treatment with recombinant galectin-1 in the efferent phase of autoimmune ocular inflammation results in increased IL-10 and TGF-β production and expansion of regulatory T cells in vivo [43]. Interestingly, recent studies demonstrated that galectin-1 and -10 are overexpressed in regulatory T cells, and are critical for the suppressive activity of these cells [49,50]. Further studies are needed to establish a role of galectin-carbohydrate lattices at synapse formation between regulatory and effector T cells.…”

Section: Galectin-glycoprotein Lattices In T Cell Functionsmentioning

confidence: 87%

Functions of cell surface galectin-glycoprotein lattices

Rabinovich

Toscano

Jackson

et al. 2007

Current Opinion in Structural Biology

361

318

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Programmed remodeling of cell surface glycans by the sequential action of specific glycosyltransferases, can control biological processes by generating or masking ligands for endogenous lectins. Galectins, a family of animal lectins with affinity for β-galactosides, can form multivalent complexes with cell surface glycoconjugates and deliver a variety of intracellular signals to modulate cell activation, differentiation, and survival. Recent efforts involving genetic or biochemical manipulation of O-and N-glycosylation pathways, as well as blockade of the synthesis of endogenous galectins, have illuminated essential roles for galectin-glycoprotein lattices in the control of biological processes including receptor turnover and endocytosis, host-pathogen interactions and immune cell activation and homeostasis.

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Human CD4+CD25+ regulatory T cells: proteome analysis identifies galectin-10 as a novel marker essential for their anergy and suppressive function

Cited by 183 publications

References 35 publications

Malignant Tregs express low molecular splice forms of FOXP3 in Sézary syndrome

Malignant Tregs express low molecular splice forms of FOXP3 in Sézary syndrome

Dependence on nuclear factor of activated T-cells (NFAT) levels discriminates conventional T cells from Foxp3 ⁺ regulatory T cells

Functions of cell surface galectin-glycoprotein lattices

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Human CD4+CD25+ regulatory T cells: proteome analysis identifies galectin-10 as a novel marker essential for their anergy and suppressive function

Cited by 183 publications

References 35 publications

Malignant Tregs express low molecular splice forms of FOXP3 in Sézary syndrome

Malignant Tregs express low molecular splice forms of FOXP3 in Sézary syndrome

Dependence on nuclear factor of activated T-cells (NFAT) levels discriminates conventional T cells from Foxp3 + regulatory T cells

Functions of cell surface galectin-glycoprotein lattices

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Dependence on nuclear factor of activated T-cells (NFAT) levels discriminates conventional T cells from Foxp3 ⁺ regulatory T cells