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

• Published in: The Journal of biological chemistry Vol. 294; no. 7; pp. 2397 - 2406
• Main Authors: Piccirillo, Ann R., Cattley, Richard T., D'Cruz, Louise M., Hawse, William F.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 15.02.2019; American Society for Biochemistry and Molecular Biology
• Subjects: Acetylation; acetyllysine; adaptive immunity; Animals; bromo domain; CD8+ T cell; CD8-Positive T-Lymphocytes - cytology; CD8-Positive T-Lymphocytes - immunology; Cell Differentiation - genetics; Cell Differentiation - immunology; CREB binding protein; CREB-Binding Protein - genetics; CREB-Binding Protein - immunology; cytokine; differentiation; Enzyme Activation - genetics; Enzyme Activation - immunology; histone; Histones - genetics; Histones - immunology; immune response; Immunologic Memory; Immunology; infection; Jak2; Janus kinase (JAK); Janus Kinase 2 - genetics; Janus Kinase 2 - immunology; kinase signaling; memory T cell; Mice; Mice, Knockout; Phosphorylation - genetics; Phosphorylation - immunology; proteomics; signal transduction; Signal Transduction - genetics; Signal Transduction - immunology; T-cell; T-cell receptor (TCR); cytokine; infection; memory T cell; differentiation; T-cell; proteomics; signal transduction; kinase signaling; acetyllysine; CD8+ T cell; adaptive immunity; bromo domain; T-cell receptor (TCR); immune response; CREB binding protein; histone; Janus kinase (JAK); Jak2
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.RA118.006977

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.