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Cutting Edge: Two Distinct Motifs within the Fas Ligand Tail Regulate Fas Ligand-Mediated Costimulation¹

Mingyi Sun^*, Shinhee Lee^*, Saoussen Karray^2,, Matthieu Levi-Strauss^3,, Kristina T. Ames^* and Pamela J. Fink^4,*

^* Department of Immunology, University of Washington, Seattle, WA 98195; and Institut National de la Santé et de la Recherche Médicale (INSERM) Unité 580, Hôpital Necker, Paris, France

The cytoplasmic domain of Fas ligand is sufficient to costimulate CD8⁺ T cells by driving Fas ligand recruitment into lipid rafts and association with select Src homology 3-containing proteins, activating PI3K and MAPK pathways, mediating nuclear translocation of the transcription factors NFAT and AP-1, and enhancing IFN- production and Ag-specific CD8⁺ T cell proliferation. We now show that Fas ligand molecules lacking amino acids 45–54 in the proline-rich region of the cytoplasmic domain fail to costimulate but serve as effective death inducers. Death induction and costimulation by Fas ligand are therefore clearly separable functions. Further, upon Fas ligand-mediated costimulation, casein kinase I phosphorylates Fas ligand, in which two conserved casein kinase I binding sites regulate NFAT activation and costimulation. These results help resolve how one molecule can serve as a double-edged immunomodulator by directing discrete biological consequences.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This work was funded by National Institutes of Health Grant AI 44130 (to P.J.F.) and by a predoctoral training grant from the Cancer Research Institute (to M.S.).

² Current address: INSERM Unité 753, Institut Gustave Roussy, Villejuif, France

³ Current address: INSERM SC11-Orphanet, Paris, France

⁴ Address correspondence and reprint requests to Dr. Pamela J. Fink, University of Washington, Department of Immunology, I-607H Health Sciences Center, Campus Box 357650, Seattle, WA 98195. E-mail address: pfink{at}u.washington.edu

⁵ Abbreviations used in this paper: TNFR, TNF receptor; 7-AAD, 7-aminoactinomycin D; B6, C57BL/6; CID, chemical inducers of dimerization; CKI, casein kinase I; EC, extracellular; FasL, Fas ligand; FKBP3, three FK506 binding domains; HA, hemagglutinin; lpr, MRL-Fas^lpr; M, myristoylation-target domain; SH3, Src homology 3; TM, transmembrane domain; WT, wild type.