LYP inhibits T cell activation when dissociated from CSK

Lymphoid tyrosine phosphatase (LYP) and C-terminal Src kinase (CSK) are negative regulators of signaling mediated through the T cell antigen receptor (TCR) and are thought to act in a cooperative manner when forming a complex. Here, we studied the spatio-temporal dynamics of the LYP/CSK complex in T cells. We demonstrate that dissociation of this complex is necessary for recruitment of LYP to the plasma membrane, where it down-modulates TCR signaling. Development of a potent and selective chemical probe of LYP confirmed that LYP inhibits T cell activation when removed from CSK. Our findings may explain the reduced TCR-mediated signaling associated with a single nucleotide polymorphism, which confers increased risk for certain autoimmune diseases, including type 1 diabetes and rheumatoid arthritis, and results in expression of a LYP allele that is unable to bind CSK. Our compound also represents a starting point for the development of a LYP-based treatment of autoimmunity.