Identification of a regulatory T cell specific cell surface molecule that mediates suppressive signals and induces Foxp3 expression.
Regulatory T (T(reg)) cells control immune activation and maintain tolerance. How T(regs) mediate their suppressive function is unclear. Here we identified a cell surface molecule, called GARP, (or LRRC32), which within T cells is specifically expressed in T(regs) activated through the T cell receptor (TCR). Ectopic expression of GARP in human naïve T (T(N)) cells inhibited their proliferation and cytokine secretion upon TCR activation. Remarkably, GARP over-expression in T(N) cells induced expression of T(reg) master transcription factor Foxp3 and endowed them with a partial suppressive function. The extracellular but not the cytoplasmic region of GARP, was necessary for these functions. Silencing Foxp3 in human T(reg) cells reduced expression of GARP and attenuated their suppressive function. However, GARP function was not affected when Foxp3 was downregulated in GARP-overexpressing cells, while silencing GARP in Foxp3-overexpressing cells reduced their suppressive activity. These findings reveal a novel cell surface molecule-mediated regulatory mechanism, with implications for modulating aberrant immune responses.
Wang
Rui
R
Department of Microbiology, New York University School of Medicine, New York, New York, United States of America.
Wan
Qi
Q
Kozhaya
Lina
L
Fujii
Hodaka
H
Unutmaz
Derya
D
D000818:Animals; D002462:Cell Membrane / Q000378:metabolism*; D049109:Cell Proliferation; D016207:Cytokines / Q000378:metabolism; D003593:Cytoplasm / Q000378:metabolism; D051858:Forkhead Transcription Factors / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D008565:Membrane Proteins / Q000378:metabolism / Q000502:physiology*; D051379:Mice; D008954:Models, Biological; D009000:Monocytes / Q000378:metabolism; D011948:Receptors, Antigen, T-Cell / Q000378:metabolism; D050378:T-Lymphocytes, Regulatory / Q000166:cytology* / Q000378:metabolism
D016207:Cytokines; C418974:FOXP3 protein, human; D051858:Forkhead Transcription Factors; C498833:Foxp3 protein, mouse; C087215:LRRC32 protein, human; C484196:Lrrc32 protein, mouse; D008565:Membrane Proteins; D011948:Receptors, Antigen, T-Cell