The dual specificity phosphatase 2 act as distal regulatory node in T cell signaling.

The mitogen-activated protein kinases (MAPKs) are critical signaling molecules that regulate T cell development, activation, and function. While the MAPK activation is well-characterized, the role of phosphatases as negative regulators remain incompletely understood. This study aimed to comprehensively investigate the role of phosphatases which regulate MAPK pathway activity in human T cells. The dual-specificity phosphatase 2 (DUSP2) was determined as a key negative regulator of ERK1/2, p38, and to a lesser extent of JNK1/2 in human T cells. Loss of DUSP2 is partly compensated by the inducible nuclear phosphatase DUSP5 whose expression is driven by the ERK1/2-dependent transcription factor EGR1, forming a negative feedback loop that modulates MAPK signaling. Functional studies reveal that the ERK1/2-EGR1-DUSP axis regulates the IL-2 production of T cells. Together, these findings suggest a critical role of the ERK1/2-EGR1-DUSP2 axis in fine-tuning MAPK activity and cytokine production during T cell activation.