Lck Domains Differentially Contribute to Pre–T Cell Receptor (Tcr)–And TCR-α/β–Regulated Developmental Transitions

Maturational changes at the CD4⁻CD8⁻ double negative (DN) to CD4⁺CD8⁺ double positive (DP) transition are dependent on signals generated via the pre–T cell receptor (TCR) and the nonreceptor protein tyrosine kinase p56^lck (Lck). How Lck activities are stimulated or relayed after pre-TCR formation remains obscure. Our structure–function mapping of Lck thymopoietic properties reveals that the noncatalytic domains of Lck are specialized to signal efficient cellular expansion at DN to DP transition. Moreover, although substitution of the Lck catalytic domain with FynT sequences minimally impacts DP development, single positive thymocytes are most efficiently produced in the presence of kinases containing both the NH₂-terminal and catalytic regions of Lck. These findings demonstrate that the Lck structure is uniquely adapted to mediate signals at both major transitions in thymopoiesis.