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.
Lückerath
Katharina
K
Chemotherapeutisches Forschungsinstitut Georg-Speyer-Haus, Frankfurt, Germany.
Kirkin
Vladimir
V
Melzer
Inga Maria
IM
Thalheimer
Frederic B
FB
Siele
Dagmar
D
Milani
Wiebke
W
Adler
Thure
T
Aguilar-Pimentel
Antonio
A
Horsch
Marion
M
Michel
Geert
G
Beckers
Johannes
J
Busch
Dirk H
DH
Ollert
Markus
M
Gailus-Durner
Valerie
V
Fuchs
Helmut
H
Hrabe de Angelis
Martin
M
Staal
Frank J T
FJ
Rajalingam
Krishnaraj
K
Hueber
Anne-Odile
AO
Strobl
Lothar J
LJ
Zimber-Strobl
Ursula
U
Zörnig
Martin
M
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