Histone acetyltransferases (HATs) regulate inducible transcription in multiple cellular processes and during inflammatory and immune response. However, the functions of general control nonrepressed–protein 5 (Gcn5), an evolutionarily conserved HAT from yeast to human, in immune regulation remain unappreciated. In this study, we conditionally deleted Gcn5 (encoded by the Kat2a gene) specifically in T lymphocytes by crossing floxed Gcn5 and Lck-Cre mice, and demonstrated that Gcn5 plays important roles in multiple stages of T cell functions including development, clonal expansion, and differentiation. Loss of Gcn5 functions impaired T cell proliferation, IL-2 production, and Th1/Th17, but not Th2 and regulatory T cell differentiation. Gcn5 is recruited onto the il-2 promoter by interacting with the NFAT in T cells upon TCR stimulation. Interestingly, instead of directly acetylating NFAT, Gcn5 catalyzes histone H3 lysine H9 acetylation to promote IL-2 production. T cell–specific suppression of Gcn5 partially protected mice from myelin oligodendrocyte glycoprotein–induced experimental autoimmune encephalomyelitis, an experimental model for human multiple sclerosis. Our study reveals previously unknown physiological functions for Gcn5 and a molecular mechanism underlying these functions in regulating T cell immunity. Hence Gcn5 may be an important new target for autoimmune disease therapy.
This work was supported by National Institutes of Health Grants R01 AI079056 (to D.F.) and R01 GM067718 (to S.Y.R.D.).
The online version of this article contains supplemental material.
- Received February 22, 2016.
- Accepted March 20, 2017.
- Copyright © 2017 by The American Association of Immunologists, Inc.