Immune modulation by Fas ligand reverse signaling: lymphocyte proliferation is attenuated by the intracellular Fas ligand domain.
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 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 wild-type 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 phospholipase C γ, protein kinase C, and extracellular signal-regulated kinase 1/2. We also demonstrate that the FasL ICD interacts with the transcription factor lymphoid-enhancer binding factor-1 and inhibits lymphoid-enhancer binding factor-1-dependent transcription. In vivo, plasma cell numbers, generation of germinal center B cells, and, consequently, production of antigen-specific immunoglobulin M antibodies in response to immunization with T cell-dependent or T cell-independent antigen are negatively affected in presence of the FasL ICD, suggesting that FasL reverse signaling participates in negative fine-tuning of certain immune responses.
Chemotherapeutisches Forschungsinstitut Georg-Speyer-Haus, Frankfurt, Germany.
Katharina
K
Lückerath
Vladimir
V
Kirkin
Inga Maria
IM
Melzer
Frederic B
FB
Thalheimer
Dagmar
D
Siele
Wiebke
W
Milani
Thure
T
Adler
Antonio
A
Aguilar-Pimentel
Marion
M
Horsch
Geert
G
Michel
Johannes
J
Beckers
Dirk H
DH
Busch
Markus
M
Ollert
Valerie
V
Gailus-Durner
Helmut
H
Fuchs
Martin
M
Hrabe de Angelis
Frank J T
FJ
Staal
Krishnaraj
K
Rajalingam
Anne-Odile
AO
Hueber
Lothar J
LJ
Strobl
Ursula
U
Zimber-Strobl
Martin
M
Zörnig
D000818:Animals; D001402:B-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism*; D049109:Cell Proliferation; D053222:Fas Ligand Protein / Q000276:immunology / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000276:immunology; D055879:Gene Knock-In Techniques; D056747:Immunomodulation / Q000276:immunology*; D008213:Lymphocyte Activation / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013601:T-Lymphocytes / Q000166:cytology / Q000276:immunology / Q000378:metabolism*
D053222:Fas Ligand Protein; C505658:Fasl protein, mouse