Germinal Center Cytokines Driven Epigenetic Control of Epstein-Barr Virus Latency Gene Expression.

A longstanding question has remained how Epstein-Barr virus (EBV) epigenetically switches between latency programs as it navigates the B-cell compartment. EBV uses its latency III program to stimulate newly infected B cell growth and then trafficking into secondary lymphoid tissue germinal centers (GC). In latency III, the viral C promoter stimulates expression of six Epstein-Barr nuclear antigens (EBNA) that in turn induce two latent membrane proteins (LMP). However, knowledge has remained incomplete about how GC microenvironmental cues trigger switching to latency II, where only one EBNA and two LMP are expressed, a program observed in Hodgkin lymphoma. Building on prior evidence that GC cytokines are a major cue, we systematically tested effects of cytokines secreted by GC-resident T follicular helper and follicular dendritic cells on EBV latency gene expression and on epigenetic remodeling of their promoters. This highlighted that a range of GC cytokines repress latency III EBNA, while only several support LMP1 expression, major events in the transition between the latency III and II programs. We identified key downstream roles of JAK/STAT signaling in relaying cytokine signals to the EBV epigenome, including obligatory STAT3 and 5 roles in rewiring of C and LMP promoter histone epigenetic marks.