A ThPOK-LRF transcriptional node maintains the integrity and effector potential of post-thymic CD4⁺ T cells

The transcription factor ThPOK promotes CD4⁺ T cell differentiation in the thymus. Here, using a mouse strain that allows post-thymic gene deletion, we show that ThPOK maintains CD4⁺ T lineage integrity and couples effector differentiation to environmental cues after antigenic stimulation. ThPOK preserved the integrity and amplitude of effector responses and was required for proper differentiation of types 1 and 2 helper T cells in vivo by restraining the expression and function of Runx3, a nuclear factor crucial for cytotoxic T cell differentiation. The transcription factor LRF acts redundantly with ThPOK to prevent the transdifferentiation of mature CD4⁺ T cells into CD8⁺ T cells. As such, the ThPOK-LRF transcriptional module was essential for CD4⁺ T cell integrity and responses.