Immune modulation by Fas ligand reverse signaling: Lymphocyte proliferation is attenuated by the intracellular Fas ligand domain.
Blood 117, 519-529 (2011)
Fas Ligand (FasL) not only induces apoptosis in Fas receptor-bearing target cells, it is also able to transmit signals into the FasL-expressing cell via its intracellular domain (ICD). Recently, we described a Notch-like proteolytic processing of FasL that leads to the release of the FasL intracellular domain (ICD) into the cytoplasm and subsequent translocation into the nucleus where it may influence gene transcription. To study the molecular mechanism underlying such reverse FasL signaling in detail and to analyze its physiological importance in vivo, we established a knockout/knockin mouse model in which wildtype FasL was replaced with a deletion mutant lacking the ICD. Our results demonstrate that FasL ICD signaling impairs activation-induced proliferation in B and T cells by diminishing phosphorylation of PLCγ, PKC and ERK1/2. We also demonstrate that the FasL ICD interacts with the transcription factor Lymphoid-enhancer binding factor-1 (Lef-1) and inhibits Lef-1-dependent transcription. In vivo, plasma cell numbers, generation of germinal center B cells and, consequently, production of antigen-specific IgM antibodies in response to immunization with T cell-dependent (TD) or T cell-independent (TI) antigen are negatively affected in presence of the FasL ICD, suggesting that FasL reverse signaling participates in negative fine-tuning of certain immune responses.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter PROTEIN-TYROSINE-PHOSPHATASE; T-CELLS; B-CELLS; SECRETORY LYSOSOMES; CYTOPLASMIC TAIL; SCHWANN-CELLS; EXPRESSION; ACTIVATION; DEATH; WNT
ISSN (print) / ISBN 0006-4971
Quellenangaben Band: 117, Heft: 2, Seiten: 519-529
Verlag American Society of Hematology, HighWire Press