Known and potential functions for the SLP-76 adapter protein in regulating T-cell activation and development

The hematopoietic adapter protein SLP-76 is a critical component of multiple biochemical signaling 'circuits' in T cells that integrate proximal signaling events initiated by ligation of the T-cell receptor (TCR) into more distal pathways. Given the important role ascribed to TCR signaling in directing the outcome of thymocyte selection, it seems likely that SLP-76 may also function in signaling pathways that ultimately impact the establishment of the peripheral T-cell repertoire. It is generally accepted that the peripheral T-cell repertoire is selected in large part during T-cell development in the thymus. Molecular interactions between the TCR and self-peptide/major histocompatibility complexes expressed on thymic stromal elements dictate the fate of developing thymocytes. Thymocyte survival and further maturation (positive selection) require an active signal delivered to the cell as a consequence of TCR ligation. This raises the intriguing question of how a thymocyte can, for a narrow window of developmental time, obtain responsiveness to self while maintaining tolerance to these same determinants upon export to the periphery. This article reviews the current literature describing SLP-76-dependent signaling pathways in mature T cells and developing thymocytes. A potential role for this critical signaling intermediate in integrating signals leading to positive and negative selection of the peripheral T-cell repertoire is also discussed.