Effective Priming of Herpes Simplex Virus-Specific CD8 ⁺ T Cells In Vivo Does Not Require Infected Dendritic Cells

Abstract

Resolution of virus infections depends on the priming of virus-specific CD8 T cells by dendritic cells (DC). While this process requires major histocompatibility complex (MHC) class I-restricted antigen presentation by DC, the relative contribution to CD8 T cell priming by infected DC is less clear. We have addressed this question in the context of a peripheral infection with herpes simplex virus 1 (HSV). Assessing the endogenous, polyclonal HSV-specific CD8 T cell response, we found that effective T cell priming depended on the presence of DC subsets specialized in cross-presentation, while Langerhans cells and plasmacytoid DC were dispensable. Utilizing a novel mouse model that allows for the elimination of infected DC, we also demonstrated that this requirement for cross-presenting DC was not related to their infection but instead reflected their capacity to cross-present HSV-derived antigen. Taking the results together, this study shows that infected DC are not required for effective CD8 T cell priming during a peripheral virus infection. The ability of some DC to present viral antigen to CD8 T cells without being infected is thought to enable the host to induce killer T cells even when viruses evade or kill infected DC. However, direct experimental proof for this notion has remained elusive. The work described in this study characterizes the role that different DC play in the induction of virus-specific killer T cell responses and, critically, introduces a novel mouse model that allows for the selective elimination of infected DC Our finding that HSV-specific CD8 T cells can be fully primed in the absence of DC infection shows that cross-presentation by DC is indeed sufficient for effective CD8 T cell priming during a peripheral virus infection.

Nuclear response to divergent mitochondrial DNA genotypes modulates the interferon immune response

“…Adaptive immunity, such as T cells that are involved in viral clearance, is initiated from day 2 onwards in the skin-draining lymph nodes [ 30 , 37 ]. The immune system of wild-type mice generally can clear the virus from the skin within 7 to 8 days, whereas mice unable to respond to type I interferons show increased viral titers, spread of the virus to the central nervous system and succumb to the infection [ 38 , 39 ].…”

How Human Herpesviruses Subvert Dendritic Cell Biology and Function

“…Moreover, there is strong evidence that bystander migratory submucosal and lymph node-resident DCs sequentially (cross-) present HSV-derived antigens in the lymph node. By contrast, directly infected DCs are most likely not involved in the activation of CD4 + and CD8 + T lymphocytes [188,189,191,[231][232][233][234].…”

How dendritic cells sense and respond to viral infections

“…Coupled with CD4 + T-cell licensing, it is XCR1 + DCs that activate the subsequent CD8 + T-cell adaptive response. Indeed, many studies highlight the importance of cross-presenting DCs in peripheral HSV infections in both humans and mice [205][206][207][208][209][210][211][212][213][214]. Another important subset of DCs with a remarkable antiviral function is the pDCs.…”