Activation of naïve CD4 ⁺ T cells re-tunes STAT1 signaling to deliver unique cytokine responses in memory CD4 ⁺ T cells

The cytokine IL-6 controls the survival, proliferation and effector characteristics of lymphocytes through activation of the transcription factors STAT1 and STAT3. While STAT3 activity is an ever-present feature of IL-6 signaling in CD4 ⁺ T cells, prior activation via the T cell antigen receptor limits IL-6’s control of STAT1 in effector and memory populations. Here we found that phosphorylation of STAT1 in response to IL-6 was regulated by the tyrosine phosphatases PTPN2 and PTPN22 expressed in response to the activation of naïve CD4 ⁺ T cells. Transcriptomics and chromatin immunoprecipitation–sequencing (ChIP-seq) of IL-6 responses in naïve and effector memory CD4 ⁺ T cells showed how the suppression of STAT1 activation shaped the functional identity and effector characteristics of memory CD4 ⁺ T cells. Thus, tyrosine phosphatases induced by the activation of naïve T cells determine the way activated or memory CD4 ⁺ T cells sense and interpret cytokine signals.