Open AccessApoptotic Effects of Antilymphocyte Globulins on Human Pro-inflammatory CD4+CD28− T-cells
Author(s) -
Christina Duftner,
Christian Dejaco,
Paul Hengster,
Klaudija Bijuklic,
Michael Joannidis,
Raimund Margreiter,
Michael Schirmer
Publication year - 2012
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0033939
Subject(s) - cd28 , il 2 receptor , microbiology and biotechnology , cytotoxic t cell , biology , apoptosis , t cell , interleukin 21 , immunology , chemistry , immune system , in vitro , biochemistry
Background Pro-inflammatory, cytotoxic CD4 + CD28 − T-cells with known defects in apoptosis have been investigated as markers of premature immuno-senescence in various immune-mediated diseases. In this study we evaluated the influence of polyclonal antilymphocyte globulins (ATG-Fresenius, ATG-F) on CD4 + CD28 − T-cells in vivo and in vitro . Principal Findings Surface and intracellular three colour fluorescence activated cell sorting analyses of peripheral blood mononuclear cells from 16 consecutive transplant recipients and short-term cell lines were performed. In vivo , peripheral levels of CD3 + CD4 + CD28 − T-cells decreased from 3.7±7.1% before to 0±0% six hours after ATG-F application (P = 0.043) in 5 ATG-F treated but not in 11 control patients (2.9±2.9% vs. 3.9±3.0%). In vitro , ATG-F induced apoptosis even in CD4 + CD28 − T-cells, which was 4.3-times higher than in CD4 + CD28 + T-cells. ATG-F evoked apoptosis was partially reversed by the broad-spectrum caspase inhibitor benzyloxycarbonyl (Cbz)-Val-Ala-Asp(OMe)-fluoromethylketone (zVAD-fmk) and prednisolon-21-hydrogensuccinate. ATG-F triggered CD25 expression and production of pro-inflammatory cytokines, and induced down-regulation of the type 1 chemokine receptors CXCR-3, CCR-5, CX3CR-1 and the central memory adhesion molecule CD62L predominately in CD4 + CD28 − T-cells. Conclusion In summary, in vivo depletion of peripheral CD3 + CD4 + CD28 − T-cells by ATG-F in transplant recipients was paralleled in vitro by ATG-F induced apoptosis. CD25 expression and chemokine receptor down-regulation in CD4 + CD28 − T-cells only partly explain the underlying mechanism.