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 T-cell receptor activation limits the IL-6 control of STAT1 in effector and memory populations. Here we show that STAT1 phosphorylation in response to IL-6 was regulated by protein tyrosine phosphatases (PTPN2, PTPN22) expressed in response to the activation of naïve CD4(+) T cells. Transcriptomic and chromatin immunoprecipitation-sequencing 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, protein tyrosine phosphatases induced by activation of naïve T cells determined the way activated or memory CD4(+) T cells sensed and interpreted cytokine signals.