Non-equivalent antigen presenting capabilities of dendritic cells and macrophages in generating brain-infiltrating CD8 + T cell responses

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.

Robust Control of a Brain-Persisting Parasite through MHC I Presentation by Infected Neurons

“…Studies in viral infections uncovered a possible interplay between astrocytes and CD8 T cells (Xie and Yang, 2015). Thanks to the above-described mouse model and to a recently published floxed K b system (Malo et al, 2018), it will now be possible to explore the role(s) of MHC I presentation by CNSresident cells in homeostasis and disease. In the case of chronic T. gondii infection, these models may be useful to better understand how brain function is impacted by this widespread parasite.…”

Conditional silencing of H-2Dbclass I molecule expression on dendritic cells modulates the protective and pathogenic kinetics of virus-antigen specific CD8 T cell responses during Theiler’s Virus infection

“…The novel H-2D b cKO transgenic mouse system has laid the groundwork to study the crucial role for DCs and other APC subsets in CD8 T cell priming against CNS pathogens without disrupting other functions of these cell types, such as CD4 T cell priming or cytokine secretion. The presently described H-2D b cKO mouse, in conjunction with our previously published H-2K b cKO mouse, enables assessment of antigen presentation in disease models [49]. Here, we have articulated the requirement for CD11c+ cells in priming acute CD8 T cell responses against intracranial infection by the picornavirus TMEV and shown that LysM+ APCs play a subordinate role in this process.…”

“…A study conducted by our research program in parallel to the one currently presented, utilizing the LysM-cre system in K b LoxP transgenic animals, had similar results in regards to the relative importance of MΦs in CD8 T cell priming. Conditional depletion of H-2K b based antigen presentation ability in MΦs resulted in no defect in the priming of CD8 T cells at 7 dpi against the K b :OVA epitope, which served as the immunodominant epitope in the engineered OVA-TMEV [49]. Again, similar to what has been put forward in regards to the present study utilizing the D b allele and a natural viral epitope, it is possible that the contribution of any potential MΦ populations to priming this antiviral CD8 T cell response are minimal in comparison with those of CD11c+ cells and are therefore masked as long as DCs remain antigen presentation competent [49].…”

“…Confocal analyses were conducted as previously reported [49]. The right brain hemispheres taken from FITC-albumin injected animals were fresh frozen at −80°C.…”

“…Flow cytometric measurements were conducted as previously published [49, 64]. Spleens and thymi harvested from euthanized animals were crushed through a 70um filter into 10mL RPMI to create a single cell suspension.…”