Epigenetic Maintenance of Acquired Gene Expression Programs during Memory CD8 T Cell Homeostasis

Abstract

Memory CD8 T cells have a unique ability to provide lifelong immunity against pathogens containing their cognate epitope. Because of their ability to provide lifelong protection, the generation of memory T cells is now a major focus for current vaccination or adoptive cell therapy approaches to treat chronic viral infections and cancer. It is now clear that maintenance of memory CD8 T cells occurs through a process of antigen-independent homeostatic proliferation, which is regulated in part by the gamma chain cytokines IL-7 and IL-15. Here, we will describe the role of these cytokines in the survival and self-renewal of memory CD8 T cells. Further, we will describe the role of epigenetics in the maintenance of acquired functions among memory CD8 T cells during homeostatic proliferation.

Keywords: CD8 T cells; cytokines; epigenetic regulation; homeostasis; immunological memory.

Figure 1

The family of common gamma chain cytokines and their receptors. The common gamma chain cytokine receptors are depicted in this cartoon showing IL-2Rγ (CD132) as the common subunit in all the receptors. Each receptor has its unique subunit that forms a heterodimer or heterotrimer receptor complex with the common gamma chain subunit. IL-4R, IL-7Rα, IL-9R, and IL-21R subunits dimerize with the common gamma chain subunit to form heterodimers that bind IL-4, IL-7, IL-9, and IL-21 cytokines, respectively. IL-2 and IL-15 receptors share two subunits, IL-2Rγ and IL-2Rβ, which trimerize with IL-2Rα or IL-15Rα to form the IL-2 or IL-15 receptor complex, respectively. The binding of each cytokine to its receptor complex results in phosphorylation of JAK1 and JAK3. The activated JAKs activate different STAT members, which then migrate to the nucleus to induce or inhibit expression of specific target genes.

Figure 2

The effect of IL-7/15 on memory CD8 T cell epigenetic programs. (A) IL-7/15-mediated signaling and epigenetic propagation during homeostatic proliferation. IL-7 and IL-15 are expressed by hematopoietic and non-hematopoietic cells resulting in survival and proliferation of memory CD8 T cells. During memory CD8 T cell homeostatic proliferation, effector-associated programs, including IFNg, are maintained over several rounds of cell division while other programs such as CCR7 remain plastic during cell division. (B) Hypothetical model for selective modification of epigenetic programs during memory T cell self-renewal. Following IL-7 and IL-15 binding to their perspective receptors, activated JAK1 and JAK3 signaling proteins phosphorylate different members of STAT family. Activated STATs may induce or inhibit expression of key epigenetic enzymes, including DNA methyl transferases (DNMTs) and dioxygeneases, that result in de novo DNA methylation, maintenance, or demethylation of regulatory regions at target genes.