Infected Cd8 Alpha(-) Dendritic Cells Are The Predominant Source Of Il-10 During Establishment Of Persistent Viral Infection

Interleukin-10 (IL-10) is an important factor involved in T-cell dysfunction during persistent viral infection. Although several factors can negatively regulate T-cell activity, targeting of the IL-10 pathway alone is sufficient to regenerate T-cell activity and increase viral control. How IL-10 mediates these effects is unclear. Here, we investigated the cellular source of IL-10 necessary for establishing T-cell exhaustion and viral persistence, using IL-10 reporter mice (VertX), cell-type-specific IL-10 and IL-10 receptor deletion mice, and bone marrow chimeric mice. During establishment of viral persistence, the cellular subset with the most prevalent expression of IL-10 was CD8 alpha(-)CD4(+) dendritic cells (DCs), which produced IL-10 with increasing kinetics until 9 d postinfection. After this time point, DCs exhibited a modest decline in percentage of IL-10(+) cells whereas B cells and CD4(+) T cells increased minimally. Further analysis of the DC population demonstrated that IL-10 was primarily expressed in infected DCs. These DCs were a notable source of IL-10 as mutant mice with a DC-specific deletion of IL-10 had significantly decreased serum levels. Interestingly, viral infection was not directly causative of IL-10 expression; rather, IL-10 production appeared to be linked to type I IFN signaling. Our findings further illuminate the contribution of DCs to the production of IL-10 and to viral persistence.