Control of lymphocyte development and activation by negative regulatory transmembrane adapter proteins

Signals emanating from antigen receptors critically regulate immune cell activation, survival, and differentiation. Transmembrane adapter proteins (TRAPs), a group of molecules that organize signaling complexes at the plasma membrane, play a pivotal role in propagating and fine-tuning antigen receptor-mediated signaling. During the last years, it has been demonstrated that most of the TRAPs possess inhibitory functions, including linker for activation of T cells (LAT), the best characterized adapter that links the T-cell receptor (TCR) to Ca(2+) flux and mitogen-activated protein kinase activation. Indeed, it appears that LAT may assemble inhibitory complexes that trigger negative feedback loops, thus terminating T-cell activation. Additionally, recent data demonstrate that SIT [Src homology 2 domain-containing phosphatase 2 (SHP2)-interacting TRAP] fine-tunes TCR-mediated signaling events and negatively regulates T-cell development and homeostasis. The experimental evidence suggests that TRAPs play a crucial role also in establishing tolerance. In fact, loss of SIT, LAX, or NTAL (non-T cell activation linker)/linker for activation of B cells (LAB) resulted in the spontaneous development of autoimmune diseases. Moreover, we recently showed that in addition to the inhibition of Src-family kinases, PAG (phosphoprotein associated with glycosphingolipid-enriched domains) is also involved in the negative regulation of Ras activation. Collectively, these data demonstrate that TRAPs are important modulators of immune cell activation and function. Finally, it appears that TRAPs possess redundant yet not completely overlapping functions.