Activated p56 lck Directs Maturation of Both CD4 and CD8 Single-Positive Thymocytes

Abstract

p56lck is a protein tyrosine kinase expressed throughout T cell development. It associates noncovalently with the cytoplasmic domains of the CD4 and CD8 coreceptor molecules and has been implicated in TCR signaling in mature T cells. Its role in early thymocyte differentiation has been demonstrated in vivo, both by targeted gene disruption and by transgene expression. Previously, we showed that expression of a dominant-negative form of p56lck in double-positive thymocytes inhibits positive selection. We now demonstrate that expression of constitutively activated p56lck (p56lckF505) accelerates the transition from the double-positive to the single-positive stage. Importantly, p56lckF505 drives survival and lineage commitment of thymocytes in the absence of TCR engagement by appropriate MHC molecules. These results indicate that activation of p56lck constitutes an early step in conveying maturational signals after TCR ligation by a positively selecting ligand. Our study provides direct in vivo evidence for the role of p56lck in regulating TCR signaling.