TCR signal transduction pathways. Engagement and stabilisation of TCR/CD3 complexes leads to a membrane-proximal cascade of tyrosine phosphorylation events that ultimately lead to the activation of kinases and transcription factors directly involved in gene transcription. Ligation of TCR and costimulatory receptors leads to activation of multiple pathways, including ERK, JNK, NF-κB, and NFAT (left panel). Impaired assembly and stability of the TCR/CD3 complex would be expected to attenuate all downstream pathways (middle panel). However, chronic TNF stimulation leads to selective uncoupling of TCR signalling, such that TCR-induced calcium/NFAT responses are impaired, while Ras/ERK activation is spared (right panel). The effects of proinflammatory cytokines on the activation of these specific pathways are not included here. ERK, extracellular signal-regulated kinase; Jnk, c-Jun N-terminal kinase; NF, nuclear factor; NFAT, nuclear factor of activated T cells; TCR, T-cell receptor.