MadSci Network: Immunology

Re: What cytokine causes the formation of FASL?

Date: Mon Jun 28 08:13:22 2004
Posted By: Ingrid Dodge, Postdoctoral Fellow
Area of science: Immunology
ID: 1080753498.Im

Dear Cikku-

FasL, now known as CD178, is the ligand for Fas (CD95). CD95 can induce apoptosis upon ligation under circumstances where the cell is not resistant to apoptosis. CD95-mediated apoptosis is a critical method to maintain immunologic homeostasis, as demonstrated by MRL/lpr mice harboring a mutation in the fas gene. MRL/lpr mice develop a systemic lupus erythematosis-like disease characterized by inappropriate lymphoproliferation (expansion of immune cells). Information about MRL/lpr mice can be found on the Jackson Labs website here.

There are also mice that are deficient in FasL, known as gld mice. These animals also exhibit lymphoproliferative defects in immune homeostasis, and information about them again is available from the Jackson Lab here. A good snapshot of information about FasL, and all CD antigens, is available from PROW here. Expression of FasL on T cells is induced post TCR activation. There is some recent evidence that cell cycle progression is necessary for FasL expression, as preventing progression reduces FasL expression (1, reviews 2 & 3). This dovetails well with the knowledge that IL-2 can drive FasL expression on T cells. In 1997, Eischen et al showed that ZAP-70 is required for FasL expression. Post-TCR ligaiton, ZAP-70 binds to phosphorylated zeta chain and initiates downstream signaling (4). CD28- mediated signaling is also implicated in upregulating FasL expression (5).

Regulation of T cell proliferation and death after activation is critical to maintaining immunologic homeostasis. Early in the immune response, the balance is tipped in favor of proliferation, through TCR ligation + costimulation - induced expression of survival factors. Later, as the T cells are competing for APCs and/or are being exposed to cytokines like IL-2 in the absence of TCR ligation, the balance is tipped towards cell death. The two reviews I cited are good references for apoptosis, but are only available through subscription. Good basic immunology texts include Immunobiology by Charles Janeway, Immunology by Kuby, and Cellular and Molecular Immunology by Abbas.

I hope this helps!

1) Torgler R, Jakob S, Ontsouka E, Nachbur U, Mueller C, Green DR, Brunner T.J Biol Chem. 2004 Jun 23 Regulation of activation-induced Fas (CD95/Apo-1) ligand expression in T cells by the cyclin B1/Cdk1 complex.
2) Brunner T, Wasem C, Torgler R, Cima I, Jakob S, Corazza N. Fas (CD95/Apo-1) ligand regulation in T cell homeostasis, cell-mediated cytotoxicity and immune pathology. Semin Immunol. 2003 Jun;15(3):167-76. Review.
3) Li-Weber M, Krammer PH. Function and regulation of the CD95 (APO- 1/Fas) ligand in the immune system. Semin Immunol. 2003 Jun;15(3):145-57. Review.
4)The Journal of Immunology Volume: 159 Number: 15 Pages: 1135-1139 08-01- 97 ZAP-70 Tyrosine Kinase Is Required for the Up-Regulation of Fas Ligand in Activation-Induced T Cell Apoptosis Christine M. Eischen, Brandi L. Williams, Weiguo Zhang, Lawrence E. Samelson, David H. Lynch, Robert T. Abraham, and Paul J. Leibson
5) Crist SA, Griffith TS, Ratliff TL. Structure/function analysis of the murine CD95L promoter reveals the identification of a novel transcriptional repressor and functional CD28 response element. J Biol Chem. 2003 Sep 19;278(38):35950-8. Epub 2003 Jul 10.

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