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GARP: a key receptor controlling FOXP3 in human regulatory T cells.

Probst-Kepper M, Geffers R, Kröger A, Viegas N, Erck C, Hecht HJ, Lünsdorf H, Roubin R, Moharregh-Khiabani D, Wagner K, Ocklenburg F, Jeron A, Garritsen H, Arstila TP, Kekäläinen E, Balling R, Hauser H, Buer J, Weiss S - J. Cell. Mol. Med. (2009)

Bottom Line: Retroviral overexpression of GARP in antigen-specific T(h) cells leads to an efficient and stable re-programming of an effector T cell towards a regulatory T cell, which involves up-regulation of FOXP3, LGALS3, LGMN and other T(reg)-associated markers.Lentiviral down-regulation of GARP in T(reg) cells significantly impaired the suppressor function and was associated with down-regulation of FOXP3.Moreover, down-regulation of FOXP3 resulted in similar phenotypic changes and down-regulation of GARP.

View Article: PubMed Central - PubMed

Affiliation: Junior Research Group for Xenotransplantation, Department of Visceral and Transplant Surgery, Hannover Medical School, Hannover, Germany.

ABSTRACT
Recent evidence suggests that regulatory pathways might control sustained high levels of FOXP3 in regulatory CD4(+)CD25(hi) T (T(reg)) cells. Based on transcriptional profiling of ex vivo activated T(reg) and helper CD4(+)CD25(-) T (T(h)) cells we have identified GARP (glycoprotein-A repetitions predominant), LGALS3 (lectin, galactoside-binding, soluble, 3) and LGMN (legumain) as novel genes implicated in human T(reg) cell function, which are induced upon T-cell receptor stimulation. Retroviral overexpression of GARP in antigen-specific T(h) cells leads to an efficient and stable re-programming of an effector T cell towards a regulatory T cell, which involves up-regulation of FOXP3, LGALS3, LGMN and other T(reg)-associated markers. In contrast, overexpression of LGALS3 and LGMN enhance FOXP3 and GARP expression, but only partially induced a regulatory phenotype. Lentiviral down-regulation of GARP in T(reg) cells significantly impaired the suppressor function and was associated with down-regulation of FOXP3. Moreover, down-regulation of FOXP3 resulted in similar phenotypic changes and down-regulation of GARP. This provides compelling evidence for a GARP-FOXP3 positive feedback loop and provides a rational molecular basis for the known difference between natural and transforming growth factor-beta induced T(reg) cells as we show here that the latter do not up-regulate GARP. In summary, we have identified GARP as a key receptor controlling FOXP3 in T(reg) cells following T-cell activation in a positive feedback loop assisted by LGALS3 and LGMN, which represents a promising new system for the therapeutic manipulation of T cells in human disease.

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Simplified model of the reprogramming or ‘transdifferentation’ of effector towards regulatory T cells via the GARP-FOXP3 positive feedback loop. The upper part illustrates the change in the ‘quality’ of TCR signalling outcome from effector (green) towards regulatory (green) TCR signalling. Thus, each TCR stimulation enhances the positive feedback indicated by the size of the feedback loop illustrated in the middle. For simplicity, other components of the regulatory network described, like LGALS3, LGMN, CD33, CD27 and CD83 or direct impairment of NFAT by GARP have been excluded. Identification of further components, fine tuning, timed-sequential expression and interconnectivity between the components of the regulatory network represents a major challenge for the molecular definition of the regulatory program.
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fig06: Simplified model of the reprogramming or ‘transdifferentation’ of effector towards regulatory T cells via the GARP-FOXP3 positive feedback loop. The upper part illustrates the change in the ‘quality’ of TCR signalling outcome from effector (green) towards regulatory (green) TCR signalling. Thus, each TCR stimulation enhances the positive feedback indicated by the size of the feedback loop illustrated in the middle. For simplicity, other components of the regulatory network described, like LGALS3, LGMN, CD33, CD27 and CD83 or direct impairment of NFAT by GARP have been excluded. Identification of further components, fine tuning, timed-sequential expression and interconnectivity between the components of the regulatory network represents a major challenge for the molecular definition of the regulatory program.

Mentions: In conclusion, we discovered GARP as a key receptor controlling FOXP3 in human CD4+CD25hi Treg cells following TCR activation. GARP is sufficient to reprogram human alloantigen-specific Th cells towards regulatory T cells via induction of sustained high levels FOXP3, presented as simplified model in Fig. 6. Furthermore, we established a positive feedback loop between GARP and FOXP3, reminiscent of positive auto-regulation ensuring formation and maintenance of high concentrations of important ‘master regulators’ of cell differentiation [51, 52]. With that GARP represents an epigenetic stabilizing system that allows the development of a permanent suppressor cell lineage, as suggested recently [53], and acts as a Treg cell-intrinsic tolerance mechanism as Treg cells are potentially auto-reactive [54]. Together, our findings provide compelling evidence of a GARP-FOXP3 positive feedback loop that is interrelated with a regulatory network including LGALS3, LGMN and other FOXP3-regulating genes like CD33, CD27 and CD83, providing a conceptual framework for the molecular definition of the regulatory program [14]. This opens up the possibility for generation of antigen-specific regulatory T cells for clinical applications. It further will provide the basis to develop new strategies and tools to induce or inhibit Treg cells in chronic infection, tumour immunotherapy, autoimmune diseases and transplantation.


GARP: a key receptor controlling FOXP3 in human regulatory T cells.

Probst-Kepper M, Geffers R, Kröger A, Viegas N, Erck C, Hecht HJ, Lünsdorf H, Roubin R, Moharregh-Khiabani D, Wagner K, Ocklenburg F, Jeron A, Garritsen H, Arstila TP, Kekäläinen E, Balling R, Hauser H, Buer J, Weiss S - J. Cell. Mol. Med. (2009)

Simplified model of the reprogramming or ‘transdifferentation’ of effector towards regulatory T cells via the GARP-FOXP3 positive feedback loop. The upper part illustrates the change in the ‘quality’ of TCR signalling outcome from effector (green) towards regulatory (green) TCR signalling. Thus, each TCR stimulation enhances the positive feedback indicated by the size of the feedback loop illustrated in the middle. For simplicity, other components of the regulatory network described, like LGALS3, LGMN, CD33, CD27 and CD83 or direct impairment of NFAT by GARP have been excluded. Identification of further components, fine tuning, timed-sequential expression and interconnectivity between the components of the regulatory network represents a major challenge for the molecular definition of the regulatory program.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4516490&req=5

fig06: Simplified model of the reprogramming or ‘transdifferentation’ of effector towards regulatory T cells via the GARP-FOXP3 positive feedback loop. The upper part illustrates the change in the ‘quality’ of TCR signalling outcome from effector (green) towards regulatory (green) TCR signalling. Thus, each TCR stimulation enhances the positive feedback indicated by the size of the feedback loop illustrated in the middle. For simplicity, other components of the regulatory network described, like LGALS3, LGMN, CD33, CD27 and CD83 or direct impairment of NFAT by GARP have been excluded. Identification of further components, fine tuning, timed-sequential expression and interconnectivity between the components of the regulatory network represents a major challenge for the molecular definition of the regulatory program.
Mentions: In conclusion, we discovered GARP as a key receptor controlling FOXP3 in human CD4+CD25hi Treg cells following TCR activation. GARP is sufficient to reprogram human alloantigen-specific Th cells towards regulatory T cells via induction of sustained high levels FOXP3, presented as simplified model in Fig. 6. Furthermore, we established a positive feedback loop between GARP and FOXP3, reminiscent of positive auto-regulation ensuring formation and maintenance of high concentrations of important ‘master regulators’ of cell differentiation [51, 52]. With that GARP represents an epigenetic stabilizing system that allows the development of a permanent suppressor cell lineage, as suggested recently [53], and acts as a Treg cell-intrinsic tolerance mechanism as Treg cells are potentially auto-reactive [54]. Together, our findings provide compelling evidence of a GARP-FOXP3 positive feedback loop that is interrelated with a regulatory network including LGALS3, LGMN and other FOXP3-regulating genes like CD33, CD27 and CD83, providing a conceptual framework for the molecular definition of the regulatory program [14]. This opens up the possibility for generation of antigen-specific regulatory T cells for clinical applications. It further will provide the basis to develop new strategies and tools to induce or inhibit Treg cells in chronic infection, tumour immunotherapy, autoimmune diseases and transplantation.

Bottom Line: Retroviral overexpression of GARP in antigen-specific T(h) cells leads to an efficient and stable re-programming of an effector T cell towards a regulatory T cell, which involves up-regulation of FOXP3, LGALS3, LGMN and other T(reg)-associated markers.Lentiviral down-regulation of GARP in T(reg) cells significantly impaired the suppressor function and was associated with down-regulation of FOXP3.Moreover, down-regulation of FOXP3 resulted in similar phenotypic changes and down-regulation of GARP.

View Article: PubMed Central - PubMed

Affiliation: Junior Research Group for Xenotransplantation, Department of Visceral and Transplant Surgery, Hannover Medical School, Hannover, Germany.

ABSTRACT
Recent evidence suggests that regulatory pathways might control sustained high levels of FOXP3 in regulatory CD4(+)CD25(hi) T (T(reg)) cells. Based on transcriptional profiling of ex vivo activated T(reg) and helper CD4(+)CD25(-) T (T(h)) cells we have identified GARP (glycoprotein-A repetitions predominant), LGALS3 (lectin, galactoside-binding, soluble, 3) and LGMN (legumain) as novel genes implicated in human T(reg) cell function, which are induced upon T-cell receptor stimulation. Retroviral overexpression of GARP in antigen-specific T(h) cells leads to an efficient and stable re-programming of an effector T cell towards a regulatory T cell, which involves up-regulation of FOXP3, LGALS3, LGMN and other T(reg)-associated markers. In contrast, overexpression of LGALS3 and LGMN enhance FOXP3 and GARP expression, but only partially induced a regulatory phenotype. Lentiviral down-regulation of GARP in T(reg) cells significantly impaired the suppressor function and was associated with down-regulation of FOXP3. Moreover, down-regulation of FOXP3 resulted in similar phenotypic changes and down-regulation of GARP. This provides compelling evidence for a GARP-FOXP3 positive feedback loop and provides a rational molecular basis for the known difference between natural and transforming growth factor-beta induced T(reg) cells as we show here that the latter do not up-regulate GARP. In summary, we have identified GARP as a key receptor controlling FOXP3 in T(reg) cells following T-cell activation in a positive feedback loop assisted by LGALS3 and LGMN, which represents a promising new system for the therapeutic manipulation of T cells in human disease.

Show MeSH
Related in: MedlinePlus