Helios promotes CD8 T cell effector differentiation by modulating IL-2 signaling 2260989

Abstract Introduction Helios (Ikzf2) belongs to a family of transcription factors that regulate lymphoid differentiation and function. In thymic-derived regulatory T cells, Helios promotes suppressive function. Previously, we observed that Helios is induced in CD8 T cells under tolerance-inducing contexts. The aim of this work was to analyze the signals that drive Helios expression and determine the roles it plays in CD8 T cell function. Methods We established an in vitro assay to identify factors that modulate Helios expression. Productive CD8 activation, achieved by high affinity ligands, inhibited Helios expression. Results In contrast, activation with low-affinity ligands led to robust Helios upregulation. Pharmacological dissection of signaling pathways indicated that activation of the IL-2-STAT5 pathway inhibited Helios induction. We analyzed Helios expression kinetics in CD8 T cells during an acute infection, where clonal expansion relies on IL-2. We observed a transitory Helios expression that peaked at 72 hours post infection. Ikzf2-deficient CD8 T cells exhibited impaired proliferation, expansion, and effector responses when exposed to cognate antigen in the context of infections (i.e. Listeria and LCMV-Arm). Transcriptomic analysis (scRNA-seq) showed that absence of Helios was associated with an expansion of cells with memory/progenitor features, suggesting that effector differentiation is altered in Ikzf2-deficient CD8 T cells during acute infections. Furthermore, transcripts encoding phosphatases implicated in IL-2 signaling were more abundant in Helios-deficient cells. Conclusion As IL-2 signaling plays a key role in the acquisition of effector functions in T cells, Helios could act as a repressor of CD8 T cell effector functions through the modulation of IL-2 signaling. In conclusion, Helios is essential for CD8 T cell effector differentiation. This regulatory mechanism could represent a novel target able to improve or restrain CD8-mediated immune responses in the context of autoimmunity or cancer. Funding Source CONAHCYT 303067 Topic Categories Immune Response Regulation: Cellular Mechanisms (IRC)