Reference : GARP: a key receptor controlling FOXP3 in human regulatory T cells
Scientific journals : Article
Human health sciences : Multidisciplinary, general & others
GARP: a key receptor controlling FOXP3 in human regulatory T cells
Probst-Kepper, M. [> >]
Geffers, R. [> >]
Kröger, A. [> >]
Viegas, N. [> >]
Erck, C. [> >]
Hecht, H. J. [> >]
Lünsdorf, H. [> >]
Roubin, R. [> >]
Moharregh-Khiabani, D. [> >]
Wagner, K. [> >]
Ocklenburg, F. [> >]
Jeron, A. [> >]
Garritsen, H. [> >]
Arstila, T. P. [> >]
Kekäläinen, E. [> >]
Balling, Rudi mailto [Helmholtz Centre for Infection Research, Inhoffenstraße, Braunschweig, Germany > Biological Systems Analysis]
Hauser, H. [> >]
Buer, J. [> >]
Weiss, S. [> >]
Journal of Cellular and Molecular Medicine
Blackwell Publishing
Yes (verified by ORBilu)
[en] positive feedback loop ; regulatory circuit ; FOXP3 ; Asparaginyl Endopeptidase ; inflammation
[en] 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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