Activation of naïve CD 4 + T cells re-tunes STAT 1 signaling to deliver unique cytokine responses in memory CD 4 + T cells

1Division of Infection & Immunity, School of Medicine, Cardiff University, Cardiff, Wales, UK. 2Systems Immunity University Research Institute, Cardiff University, Cardiff, UK. 3Monash Biomedicine Discovery Institute, Monash University, Clayton, Victoria, Australia. 4Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia. 5Centre for Experimental Medicine & Rheumatology, William Harvey Research Institute, Queen Mary’s School of Medicine & Dentistry, London, UK. 6Biomarker Discovery OMNI, Genentech Research & Early Development, South San Francisco, CA, USA. 7Department of Microbiology, Monash University, Clayton, Victoria, Australia. 8Division of Cancer & Genetics, School of Medicine, Cardiff University, Cardiff, UK. 9Brighton and Sussex Medical School, University of Sussex, Brighton, UK. 10Division of Psychological Medicine & Clinical Neuroscience, School of Medicine, Cardiff University, Cardiff, UK. 11School of Cellular and Molecular Medicine, Biomedical Sciences Building, University Walk, University of Bristol, Bristol, UK. 12These authors contributed equally: Jason P. Twohig, Ana Cardus Figueras. 13Deceased: Javier Uceda Fernandez. *e-mail: JonesSA@cf.ac.uk Naïve, activated and memory T cells display differences in their ability to respond to antigen. These include changes in proliferation, survival, sensitivity to antigen, dependence on costimulatory signals and alterations in T cell homing1. Cytokines responsible for the control of these activities often signal through receptor-associated Janus kinases (Jak proteins) that regulate cytoplasmic transcription factors termed signal transducers and activators of transcription (STAT)2. Thus, the Jak-STAT pathway senses and interprets environmental signals essential for proliferation and functional identity2. Here, we examined whether cytokine cues delivered by the Jak-STAT pathway can be adapted to fine-tune the effector properties of individual CD4+ T cell subsets. Studies of infection, inflammation, autoimmunity and cancer demonstrate that the cytokine IL-6 is essential for the generation of adaptive immunity3. Activities include the maturation and maintenance of antibody-secreting B cells, and responses that shape the effector characteristics of CD4+ helper T cells (TH). In this regard, mice lacking IL-6 often show deficiencies in T cell effector function and memory recall4–9. Studies also suggest that CD4+ T cells display differences in IL-6 responsiveness that may reflect the activation status of the T cell7,10–12. How these differences arise is currently unclear. The receptor complex responsible for IL-6 signaling consists of a type-1 cytokine receptor (IL-6R, CD126) and a signal-transducing β-receptor (gp130, CD130) subunit3. IL-6R is shed in response to CD4+ T cell activation, and inflammatory T cells from sites of disease often display low IL-6R expression7,10,12–17. IL-6 activates the latent transcription factors STAT1 and STAT3 (ref. 3). IL-6 control of STAT3 is essential for T cell recruitment and survival and maintenance of activated T cells within inflamed tissues11,14,16. These STAT3-driven responses include the transactivation of anti-apoptotic regulators and genes that determine the effector or regulatory characteristic of CD4+ T cells3,11,18. In contrast, IL-6 activation of STAT1 plays a more regulatory role and often determines the transcriptional output of STAT3 (refs. 18–21). These studies illustrate a complex interplay between STAT1 and STAT3 and emphasize how STAT1 signaling may shape the biological properties of IL-6 (refs. 18,20–24). Notably, CD4+ T cell activation has been shown to alter IL-6 signaling through STAT1 (refs. 9,11). Here we show that STAT1 phosphorylation in response to IL-6 is suppressed in activated and memory CD4+ T cells and identify protein tyrosine phosphatases as regulators of STAT1 activity. Our data further showed how this reprogramming mechanism may influence the way effector memory CD4+ T cells sense and interpret IL-6 signals in disease.