CD40.FasL inhibits human T cells: evidence for an auto-inhibitory loop-back mechanism.
A chimeric CD40.FasL (CD40-CD95L) protein was designed with the combined capacities to bind to two surface receptors on activated T cells, CD40 ligand (CD40L; CD154) and Fas receptor (CD95). CD40.FasL, once tethered to the cell surface via one of its ends, can transmit a signal via its other end. In principle, simultaneous triggering from both ends is possible, and thus there is the intriguing potential for 'auto-inhibition' if such dual triggering occurs on the same cell itself. Several lines of evidence support this mechanism: (i) CD40.FasL is cytotoxic to Fas receptor-positive cell lines of different cell lineages, (ii) CD40.FasL's function is potentiated when there is enforced expression of CD40L on target cells, (iii) CD40.FasL inhibition does not require intercellular contact, as demonstrated by soft agar clone formation and cell dilution analysis and (iv) introduction of exogenous CD40 into the system interferes with CD40.FasL inhibition. Taken together, these data are consistent with a 'loop-back' inhibitory mechanism within individual activated (CD40L and Fas receptor expressing) T cells causing suicide of these T cells. Significantly, this type of fusion protein provides a unique way to confine immunoinhibition to activated T cells.
Dranitzki-Elhalel
M
M
Nephrology and Hypertension Services, Hadassah-Hebrew University Medical Center, Jerusalem, Israel. michalelhalel@gmail.com
Huang
J H
JH
Sasson
M
M
Rachmilewitz
J
J
Parnas
M
M
Tykocinski
M L
ML
D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D001402:B-Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D017252:CD3 Complex / Q000276:immunology; D019013:CD40 Antigens / Q000235:genetics* / Q000378:metabolism; D023201:CD40 Ligand / Q000235:genetics / Q000378:metabolism; D016827:CD8 Antigens / Q000235:genetics / Q000378:metabolism; D002460:Cell Line; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D018920:Coculture Techniques; D004305:Dose-Response Relationship, Drug; D053222:Fas Ligand Protein / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D019169:Jurkat Cells; D007963:Leukocytes, Mononuclear / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D051379:Mice; D041681:NIH 3T3 Cells; D011485:Protein Binding / Q000187:drug effects; D011993:Recombinant Fusion Proteins / Q000378:metabolism / Q000494:pharmacology*; D013601:T-Lymphocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism; D014162:Transfection; D019014:fas Receptor / Q000378:metabolism
D000911:Antibodies, Monoclonal; D017252:CD3 Complex; D019013:CD40 Antigens; D016827:CD8 Antigens; D053222:Fas Ligand Protein; D011993:Recombinant Fusion Proteins; D019014:fas Receptor; D023201:CD40 Ligand