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-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-κB 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-FLIPL 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-κB activity upon TCR stimulation. These results demonstrate that c-FLIP_L is essential for T lymphocyte proliferation through an NF-KB-independent pathway. The Journal of Immunology, 2008, 180: 5506-5511.