Gerardo Suarez-Rojas: No financial relationships to disclose
Introduction/Rationale: 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.
