Histone acetyltransferase CBP is critical for conventional effector and memory T-cell differentiation in mice

Compared with naïve T cells, memory CD8⁺ T cells have a transcriptional landscape and proteome that are optimized to generate a more rapid and robust response to secondary infection. Additionally, rewired kinase signal transduction pathways likely contribute to the superior recall response of memory CD8⁺ T cells, but this idea has not been experimentally confirmed. Herein, we utilized an MS approach to identify proteins that are phosphorylated on tyrosine residues in response to Listeria-induced T-cell receptor (TCR) stimulation in both naïve and memory CD8⁺ T cells from mice and separated by fluorescence- and flow cytometry-based cell sorting. This analysis identified substantial differences in tyrosine kinase signaling networks between naïve and memory CD8⁺ T cells. We also observed that an important axis in memory CD8⁺ T cells couples Janus kinase 2 (JAK2) hyperactivation to the phosphorylation of CREB-binding protein (CBP). Functionally, JAK2-catalyzed phosphorylation enabled CBP to bind with higher affinity to acetylated histone peptides, indicating a potential epigenetic mechanism that could contribute to rapid initiation of transcriptional programs in memory CD8⁺ T cells. Moreover, we found that CBP itself is essential for conventional effector and memory CD8⁺ T-cell formation. These results indicate how signaling pathways are altered to promote CD8⁺ memory cell formation and rapid responses to and protection from repeat infections.