Open AccessGARP: a key receptor controlling FOXP3 in human regulatory T cells
Author(s) -
ProbstKepper M.,
Geffers R.,
Kröger A.,
Viegas N.,
Erck C.,
Hecht H.J.,
Lünsdorf H.,
Roubin R.,
MoharreghKhiabani D.,
Wagner K.,
Ocklenburg F.,
Jeron A.,
Garritsen H.,
Arstila T.P.,
Kekäläinen E.,
Balling R.,
Hauser H.,
Buer J.,
Weiss S.
Publication year - 2009
Publication title -
journal of cellular and molecular medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.44
H-Index - 130
eISSN - 1582-4934
pISSN - 1582-1838
DOI - 10.1111/j.1582-4934.2009.00782.x
Subject(s) - foxp3 , biology , microbiology and biotechnology , regulatory t cell , il 2 receptor , t cell , t cell receptor , effector , immune system , immunology
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‐β 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.