Fig. 1

A model of TIL anergy. The anergic state is maintained by low levels of FLICE inhibitory protein (FLIP). Arrows indicate steps in normal T cells that are sequential activation events. Blocks in the anergy pathway are indicated by blunted lines (steps 2, 5, 6, and 7). Step 1 is the activation of caspase by induction of the Fas (or TNF-α) pathway. Apoptosis can be activated by any cell in the tumor environment that expresses FasL or TNF-α; tumor, activated macrophages, or TIL. Step 2 is cleavage of TCRζ by activated effector caspases. Step 3 is the failure to activate MAP kinase, because of inactivated TCRζ. Failure to activate MAP kinase results in down-regulated cytokine transcription, loss of proliferative response to TCR ligation, failure to transit the cell cycle, and loss of effector phase CTL function, especially granule release. Step 4 is down-regulation of FLIP, since MAP kinase is inactivated. Step 5 is up-regulation of caspases in response to decreased FLIP levels. Step 6 is a block in production of death substrates putatively induced by the tumor. Step 7 is the involvement of IL-2 receptor-mediated signaling in maintenance of FLIP levels. TNF, tumor necrosis factor; TCRζ, T-cell receptor zeta; IL-2R, interleukin-2 receptor; MAP, mitogen-activated protein; CTL, cytotoxic T lymphocyte.