Notch dependent chromatin remodeling enables Gata3 binding and drives lineage specific CD8+ T cell function.

Abstract

Activation of CD8⁺ T cells enable them to control virus infections and tumors. This process involves the differentiation of naïve CD8⁺ T cells into effector and memory states, driven by specific transcription factors (TFs). Previously, we have shown that Granzyme A (Gzma) induction in activated CD8⁺ T cells depends on Gata3 and the establishment of a permissive chromatin landscape at the Gzma locus. Interestingly, Gzma expression is independent of IL-4 signaling, which typically upregulates Gata3 in CD4⁺ T cells, suggesting an alternative pathway for Gata3 induction. Here we demonstrate that Notch signals during CD8⁺ T cell activation promote Gzma expression. Inhibition of Notch signaling or loss of the Notch transactivator Rbp-j leads to reduced Gzma expression, with transcriptionally repressive chromatin at the Gzma locus. The genome targets of Gata3 differ in effector CD8⁺ T cells activated with IL-4 compared with those activated with Notch signals or isolated after IAV infection. This indicates that the signals received during CD8⁺ T cell activation can alter the chromatin landscape, affecting Gata3 function. Furthermore, Gata3 deficiency results in reduced IAV-specific CD8⁺ T cell responses and decreased Gzma expression, although the Gzma locus maintains a permissive chromatin landscape. These findings suggest that Notch signals received by virus-specific CD8⁺ T cells prepare the chromatin landscape for Gata3 binding to CD8⁺ lineage-specific gene loci, promoting effective CD8⁺ T cell immunity.