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The Long Isoform of Cellular FLIP Is Essential for T Lymphocyte Proliferation through an NF-B-Independent Pathway¹

Department of Immunology, Duke University Medical Center, Durham, NC 27710

Although the long isoform of cellular FLIP (c-FLIP_L) has been implicated in TCR-mediated signaling, its role in T cell proliferation remains controversial. Some studies have demonstrated that overexpression of c-FLIP_L promotes T cell proliferation and NF-B activation, whereas others have reported that c-FLIP_L overexpression has no effect or even inhibits T cell proliferation. To establish the role of c-FLIP_L in T lymphocyte proliferation, we have generated a conditional knockout mouse strain specifically lacking c-FLIP_L in T lymphocytes. c-FLIP_L^–/– mice exhibit severely impaired effector T cell development after Listeria monocytogenes infection in vivo and c-FLIP_L-deficient T cells display defective TCR-mediated proliferation in vitro. However, c-FLIP_L^–/– T cells exhibit normal NF-B activity upon TCR stimulation. These results demonstrate that c-FLIP_L is essential for T lymphocyte proliferation through an NF-B-independent pathway.

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 supported by National Institutes of Health Grants CA92123 and AI54683.

² Address correspondence and reprint requests to Dr. You-Wen He, Box 3010, Department of Immunology, Duke University Medical Center, Durham, NC 27710. E-mail address: he000004{at}mc.duke.edu

³ Abbreviations used in this paper: c-FLIP_L, long isoform of cellular FLIP; FADD, Fas-associated death domain protein; BAC, bacterial artificial chromosome; SP, single-positive; tg, transgenic; DNP-KLH, DNP-keyhole limpet hemocyanin; WT, wild type.

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The JI 2008 180: 5155-5156. [Full Text]  

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