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International Immunology Advance Access originally published online on February 20, 2007
International Immunology 2007 19(4):355-363; doi:10.1093/intimm/dxm001
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© The Japanese Society for Immunology. 2007. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

CD40·FasL inhibits human T cells: evidence for an auto-inhibitory loop-back mechanism

M. Dranitzki-Elhalel1, J. H. Huang2, M. Sasson3, J. Rachmilewitz4, M. Parnas1 and M. L. Tykocinski2

1 Nephrology and Hypertension Services, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
2 Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA
3 Internal Medicine, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
4 Goldyne Savad Institute of Gene Therapy, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

Correspondence to: M. Dranitzki-Elhalel; E-mail: michalelhalel{at}gmail.com

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.

Keywords: CD40-CD40L, Fas-FasL, fusion protein, apoptosis, auto-Inhibition

Transmitting editor: S. Galli

Received 7 March 2006, accepted 9 January 2007.


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