It is generally accepted that CD8 T cells play the key role to maintain HSV-1 latency in trigeminal ganglia of ocularly infected mice. Yet, comparably little is known about the role of innate immunity in establishment of viral latency. In the current study, we investigated whether CD8α DCs impact HSV-1 latency by examining latency in the trigeminal ganglia (TG) of wild-type (WT) C57BL/6 versus CD8α-/-(lack functional CD8 T cells and CD8α-/-DCs), CD8β-/-(have functional CD8α-/-T cells and CD8α+DCs), and β2m-/-(lack functional CD8 T cells but have CD8α+DCs) mice as well as BXH2 (have functional CD8 T cells but lack CD8α+DCs) versus WT C3H (have functional CD8α T cells and CD8α+DCs) mice. We also determined whether the phenotype of CD8α-/-and BXH2 mice could be restored to that of WT mice by adoptive transfer of WT CD8+T cells or bone marrow (BM) derived CD8α+DCs. Our results clearly demonstrate that CD8α DCs, rather than CD8 T cells, are responsible for enhanced viral latency and recurrences. © 2014 Mott et al.