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2015 ; 195
(6
): 2648-56
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Hepatic Stellate Cells Inhibit T Cells through Active TGF-?1 from a Cell
Surface-Bound Latent TGF-?1/GARP Complex
#MMPMID26246140
Li Y
; Kim BG
; Qian S
; Letterio JJ
; Fung JJ
; Lu L
; Lin F
J Immunol
2015[Sep]; 195
(6
): 2648-56
PMID26246140
show ga
Hepatic stellate cells (HSCs) inhibit T cells, a process that could help the
liver to maintain its immunoprivileged status. HSCs secrete latent TGF-?1, but
the detailed mechanisms by which latent TGF-?1 is activated and whether it plays
any role in HSC-mediated T cell suppression remain unclear. Glycoprotein A
repetitions predominant (GARP) is a surface marker of activated regulatory T
cells. GARP binds latent TGF-?1 for its activation, which is critical for
regulatory T cells to suppress effector T cells; however, it is still unclear
whether GARP is present on HSCs and whether it has any impact on HSC function. In
this study, we found that TGF-?1(+/-) HSCs, which produce reduced levels of
TGF-?1, showed decreased potency in inhibiting T cells. We also found that
pharmaceutical or genetic inhibition of the TGF-?1 signaling pathway reduced the
T cell-inhibiting activity of HSCs. Additionally, using isolated primary HSCs, we
demonstrated that GARP was constitutively expressed on HSCs. Blocking GARP
function or knocking down GARP expression significantly impaired the potency of
HSCs to suppress the proliferation of and IFN-? production from activated T
cells, suggesting that GARP is important for HSCs to inhibit T cells. These
results demonstrate the unexpected presence of GARP on HSCs and its significance
in regard to the ability of HSCs to activate latent TGF-?1 and thereby inhibit T
cells. Our study reveals a new mechanism for HSC-mediated immune regulation and
potentially for other conditions, such as liver fibrosis, that involve
HSC-secreted TGF-?1.
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