Distinct APC subtypes drive spatially segregated [CD4.sup.+] and [CD8.sup.+] T-cell effector activity during skin infection with HSV-1

Efficient infection control requires potent T-cell responses at sites of pathogen replication. However, the regulation of T-cell effector function in situ remains poorly understood. Here, we show key differences in the regulation of effector activity between [CD4.sup.+] and [CD8.sup.+] T-cells during skin infection with HSV-1. IFN-γ-producing [CD4.sup.+] T cells disseminated widely throughout the skin and draining lymph nodes (LN), clearly exceeding the epithelial distribution of infectious virus. By contrast, IFN-γ-producing [CD8.sup.+] T cells were only found within the infected epidermal layer of the skin and associated hair follicles. Mechanistically, while various subsets of lymphoid- and skin-derived dendritic cells (DC) elicited IFN-γ production by [CD4.sup.+] T cells, [CD8.sup.+] T cells responded exclusively to infected epidermal cells directly presenting viral antigen. Notably, uninfected cross-presenting DCs from both skin and LNs failed to trigger IFN- γ production by [CD8.sup.+] T-cells. Thus, we describe a previously unappreciated complexity in the regulation of [CD4.sup.+] and [CD8.sup.+] T-cell effector activity that is subset-specific, microanatomically distinct and involves largely non-overlapping types of antigen-presenting cells (APC).