The effector differentiation of T cells in response to infection must be carefully timed: too soon, and the effector population will be small; too late, and the infection may run out of control. In the Proceedings of the National Academy Sciences, Fearon and colleagues demonstrate a T cell–intrinsic mechanism by which these mutually exclusive imperatives of a T cell response can be controlled. Hippo signaling is a highly conserved developmental pathway that regulates organ size. The authors find that Hippo signaling is also triggered in a cell-cell contact–dependent manner after productive activation of T cells. After being activated, T cells upregulate a pair of molecules, CTLA-4 and CD80; after their mutual interaction, this leads to assembly of the Hippo pathway and then to terminal differentiation. The frequency of such cell-cell interactions naturally increases after antigen-specific expansion and therefore leads to the optimally timed appearance of effector T cells.

Proc. Natl. Acad. Sci. USA (27 June 2012) doi:10.1073/pnas.1209115109