GARP: a key receptor controlling FOXP3 in human regulatory T cells.
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.
Probst-Kepper
M
M
Junior Research Group for Xenotransplantation, Department of Visceral and Transplant Surgery, Hannover Medical School, Hannover, Germany.
Geffers
R
R
Kröger
A
A
Viegas
N
N
Erck
C
C
Hecht
H-J
HJ
Lünsdorf
H
H
Roubin
R
R
Moharregh-Khiabani
D
D
Wagner
K
K
Ocklenburg
F
F
Jeron
A
A
Garritsen
H
H
Arstila
T P
TP
Kekäläinen
E
E
Balling
R
R
Hauser
H
H
Buer
J
J
Weiss
S
S
D015496:CD4-Positive T-Lymphocytes / Q000166:cytology; D003470:Culture Media / Q000378:metabolism; D015536:Down-Regulation; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D005786:Gene Expression Regulation; D049452:Green Fluorescent Proteins / Q000737:chemistry; D006801:Humans; D053645:Interleukin-2 Receptor alpha Subunit / Q000096:biosynthesis; D015759:Ionomycin / Q000494:pharmacology; D008565:Membrane Proteins / Q000378:metabolism*; D008954:Models, Biological; D010641:Phenotype; D015398:Signal Transduction; D050378:T-Lymphocytes, Regulatory / Q000166:cytology*; D014158:Transcription, Genetic
D003470:Culture Media; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; D053645:Interleukin-2 Receptor alpha Subunit; C087215:LRRC32 protein, human; D008565:Membrane Proteins; D049452:Green Fluorescent Proteins; D015759:Ionomycin