TCR ligand discrimination is enforced by competing ERK positive and SHP-I negative feedback pathways

Functional discrimination between structurally similar self and foreign antigens is a main attribute of adaptive immunity. Here we describe two feedback mechanisms in T lymphocytes that together sharpen and amplify initial signaling differences related to the quality of T cell receptor (TCR) engagement. Weakly binding ligands predominantly trigger a negative feedback loop leading to rapid recruitment of the tyrosine phosphatase SHP-I, followed by receptor desensitization through inactivation of Lck kinase. In contrast, strongly binding ligands efficiently activate a positive feedback circuit involving Lck modification by ERK, preventing SHP-I recruitment and allowing the long-lasting signaling necessary for gene activation. The characteristics of these pathways suggest that they constitute an important part of the mechanism allowing T cells to discriminate between self and foreign ligands.