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Singer and colleagues show that the developmental fate of autoreactive CD4⁺ thymocytes is determined by the timing and duration of agonist signaling. Early agonist signaling induces clonal deletion, whereas late agonist signaling induces differentiation into Foxp3⁺ T_reg cells or IL-2⁺ T_eff cells depending on whether TGF-β disrupts TCR signaling.

To determine how T cell lineage fates are determined in the thymus, Singer and colleagues generated ‘FlipFlop’ mice with a functionally reversed T cell immune system that distinguishes TCR signal strength versus TCR signal duration.

Whether CD8-lineage specification and CD8⁺ T cell differentiation is dependent on intrathymic cytokines signaling is unclear. Singer and co-workers show that interleukin 7 specifies CD8-lineage choice and promotes the differentiation of cytotoxic-lineage T cells.

The CD4-versus-CD8 lineage ‘choice’ is a critical stage of thymocyte development. Singer and colleagues reveal that CD8 positive selection occurs in a defined time window and involves a compensatory mechanism that dynamically adjusts to TCR and cytokine signals.

Why signaling via both the receptor for interleukin 7 (IL-7R) and the T cell antigen receptor (TCR) is required for T cell homeostasis has been unclear. Singer and colleagues show that engagement of the TCR interrupts IL-7R signals to prevent a mechanism of cytokine-induced cell death.

T cells developing in the thymus are signaled during positive selection to differentiate into either CD4⁺ T cells or CD8⁺ T cells. Singer and colleagues show that CD8⁺-lineage specification is signaled exclusively by cytokines, including cytokines that do not signal via the γ_c receptor, and that these are the only signals in the thymus that upregulate the transcription factor Runx3d to direct specification to the CD8⁺ lineage.

Singer and colleagues show that let-7 microRNAs target Zbtb16 mRNA, which encodes the transcription factor PLZF, to modulate PLZF expression during the terminal differentiation of NKT cells into effector subsets.