Abstract
The contribution of antigen-presenting cell (APC) types in generating CD8+ T cell responses in the central nervous system (CNS) is not fully defined, limiting the development of vaccines and understanding of immune-mediated neuropathology. Here, we generate a transgenic mouse that enables cell-specific deletion of the H-2Kb MHC class I molecule. By deleting H-2Kb on dendritic cells and macrophages, we compare the effect of each APC in three distinct models of neuroinflammation: picornavirus infection, experimental cerebral malaria, and a syngeneic glioma. Dendritic cells and macrophages both activate CD8+ T cell responses in response to these CNS immunological challenges. However, the extent to which each of these APCs contributes to CD8+ T cell priming varies. These findings reveal distinct functions for dendritic cells and macrophages in generating CD8+ T cell responses to neurological disease.
Highlights
The contribution of antigen-presenting cell (APC) types in generating CD8+ T cell responses in the central nervous system (CNS) is not fully defined, limiting the development of vaccines and understanding of immune-mediated neuropathology
We generated cytomegalovirus promoter (CMV)-cre Kb conditional knockout (cKO) mice, which ubiquitously express cre, resulting in full Kb deletion (Fig. 1f, g). These experiments demonstrate that the transgenic Kb cKO mouse model system is functioning as expected and is appropriate to address the contribution of specific APCs in development and following antigenic challenge
Macrophages, dendritic cells, and other CNS-resident cells have each been reported to prime antigen-specific CD8+ T-cell responses[1,2,3,4,18,32,34,35]
Summary
The contribution of antigen-presenting cell (APC) types in generating CD8+ T cell responses in the central nervous system (CNS) is not fully defined, limiting the development of vaccines and understanding of immune-mediated neuropathology. MHC I molecules are almost ubiquitously expressed, and multiple cell types, including dendritic cells and macrophages, are capable of antigen presentation[13,14,15,16,18,19,20,21] Both of these cell types activate CD8+ T cells in vitro and peripherally in vivo, whether a response in the CNS is generated through a similar process is unknown[22,23]. To address the specific role of MHC I antigen presentation while leaving all APC subsets intact, we here generate a transgenic mouse that enables conditional deletion of the H-2Kb (Kb) MHC I molecule using a cre-lox system. We show a nonredundant role for MHC I antigen presentation by dendritic cells and macrophages in these model systems
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