The long isoform of cellular FLIP is essential for T lymphocyte proliferation through an NF-κB-independent pathway

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