Article (Scientific journals)
GARP: a key receptor controlling FOXP3 in human regulatory T cells
Probst-Kepper, M.; Geffers, R.; Kröger, A. et al.
2009In Journal of Cellular and Molecular Medicine, 13 (9B), p. 3343-57
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Keywords :
positive feedback loop; regulatory circuit; FOXP3; Asparaginyl Endopeptidase; inflammation
Abstract :
[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.
Disciplines :
Human health sciences: Multidisciplinary, general & others
Identifiers :
UNILU:UL-ARTICLE-2012-228
Author, co-author :
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 ;  Helmholtz Centre for Infection Research, Inhoffenstraße, Braunschweig, Germany > Biological Systems Analysis
Hauser, H.
Buer, J.
Weiss, S.
More authors (9 more) Less
Language :
English
Title :
GARP: a key receptor controlling FOXP3 in human regulatory T cells
Publication date :
2009
Journal title :
Journal of Cellular and Molecular Medicine
ISSN :
1582-1838
Publisher :
Blackwell Publishing
Volume :
13
Issue :
9B
Pages :
3343-57
Peer reviewed :
Peer reviewed
Available on ORBilu :
since 10 May 2013

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