Human T cell microparticles circulate in blood of hepatitis patients and induce fibrolytic activation of hepatic stellate cells.
Microparticles (MPs) are small cell membrane vesicles that are released from cells during apoptosis or activation. Although circulating platelet MPs have been studied in some detail, the existence and functional role of T cell MPs remain elusive. We show that blood from patients with active hepatitis C (alanine aminotransferase [ALT] level >100 IU/mL) contains elevated numbers of T cell MPs compared with patients with mild hepatitis C (ALT <40 IU/mL) and healthy controls. T cell MPs fuse with cell membranes of hepatic stellate cells (HSCs), the major effector cells for excess matrix deposition in liver fibrosis and cirrhosis. MP uptake is partly intercellular adhesion molecule 1-dependent and leads to activation of nuclear factor kappa B and extracellular signal-regulated kinases 1 and 2 and subsequent up-regulation of fibrolytic genes in HSCs, down-regulation of procollagen α1(I) messenger RNA, and blunting of profibrogenic activities of transforming growth factor β1. Ex vivo, the induced fibrolytic activity is evident in MPs derived from activated CD4+ T cells and is highest in MPs derived from activated and apoptotic CD8+ T cells. Mass spectrometry, fluorescence-activated cell sorting analysis, and function blocking antibodies revealed CD147/Emmprin as a candidate transmembrane molecule in HSC fibrolytic activation by CD8+ T cell MPs.


CONCLUSIONS
Circulating T cell MPs are a novel diagnostic marker for inflammatory liver diseases, and in vivo induction of T cell MPs may be a novel strategy to induce regression of liver fibrosis.
Division of Gastroenterology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA 02215, USA.
Miroslaw
M
Kornek
Yury
Y
Popov
Towia A
TA
Libermann
Nezam H
NH
Afdhal
Detlef
D
Schuppan
D051926:Basigin / Q000378:metabolism; D015496:CD4-Positive T-Lymphocytes / Q000502:physiology; D018414:CD8-Positive T-Lymphocytes / Q000502:physiology; D055252:Cell-Derived Microparticles / Q000502:physiology*; D015536:Down-Regulation; D055166:Hepatic Stellate Cells / Q000502:physiology*; D019698:Hepatitis C, Chronic / Q000097:blood / Q000503:physiopathology*; D006801:Humans; D018799:Intercellular Adhesion Molecule-1 / Q000502:physiology; D019169:Jurkat Cells; D008103:Liver Cirrhosis / Q000503:physiopathology*; D053773:Transforming Growth Factor beta1; D015854:Up-Regulation
C497886:BSG protein, human; D053773:Transforming Growth Factor beta1; D018799:Intercellular Adhesion Molecule-1; D051926:Basigin