Dendritic cell subset positioning governs clonal diversity and magnitude of the CD8 T cell response

Abstract

Abstract Although the molecular requirements for CD8 T cell responses have been well characterized, subunit vaccine formulations struggle to generate robust CD8 T cell immunity. One possible basis for this may be the relationship of dendritic cell (DC) subset topography to micro-anatomically dictated antigen dispersal and subsequent down-stream innate and adaptive cellular engagement. To address this issue directly in situ we utilized advanced quantitative imaging approaches (histo-cytometry) and found that protein immunization led to non-linear concentration gradients across draining lymph nodes. This graded distribution in turn affected which DC subset had access to high vs. low concentrations of antigen. Because DC subsets are specialized in MHC-I vs. MHC-II antigen processing and presentation, the result of this intersection of antigen dispersal and cell positioning was the predominant residence of MHC-I presenting DC in regions with lower antigen bioavailability. Modulating the antigen dose directly influenced the fraction of MHC-I presenting DC with access to sufficient antigen to activate T cells, allowing for direct control over the clonal diversity and magnitude of the response. These findings indicate that tissue microanatomy related to DC subset distribution and antigen dissemination within the lymph node is a critical regulator of CD8 T cell immunity. This research was supported by the Intramural Research Program of the NIH, NIAID.