Conditional silencing of the H-2Db class I molecule on CD11c+ Dendritic Cells inhibits the generation of antiviral CD8 T Cells during acute Theiler’s Murine Encephalomyelitis Virus (TMEV) infection in the CNS

Abstract

Abstract The generation of an effective antiviral CD8 T cell response is required to protect C57BL/6 mice from Theiler’s murine encephalomyelitis virus (TMEV) induced demyelinating syndrome. Our group previously defined the VP2 121-130 peptide presented in the context of the H-2Db class I molecule as the immunodominant antigen recognized by the majority of brain infiltrating CD8 T cells during acute TMEV infection. Our group also determined that this Db:VP2 121-130 epitope specific CD8 T cell response was required for virus clearance. However, the mechanism by which virus antigen-specific CD8 T cells are generated in the brain remained undefined. Therefore, our laboratory generated a novel transgenic mouse system that enables conditional ablation of the H-2Db class I gene in specific antigen presenting cell types (APCs). Previously, analysis of class I-restricted antigen presentation required genetic disruption or depletion of entire APC subsets. We used this novel Cre-Lox transgenic mouse system to define the APC required to generate the immunodominant Db:VP2 121-130 epitope specific CD8 T cell response during acute TMEV infection. In the course of this analysis, we determined that silencing of class I-restricted antigen presentation on CD11c+ dendritic cells (DCs) did not affect thymic development of CD8 T cells. However, loss of Db expression by CD11c+ DCs completely abolished the generation of Db:VP2 121-130 epitope-specific CD8 T cell responses during acute TMEV infection. These findings demonstrate the importance of DCs in generating CD8 T cell responses against a neurotropic virus. We also provide a novel transgenic mouse for future studies involving class I-restricted antigen presentation.