Spatiotemporally Distinct Interactions with Dendritic Cell Subsets Facilitates CD4+ and CD8+ T Cell Activation to Localized Viral Infection

Abstract

The dynamics of when and where CD4(+) Tcells provide help for CD8(+) Tcell priming and which dendritic cells (DCs) activate CD4(+) Tcells invivo after localized infection are poorly understood. By using a cutaneous herpes simplex virus infection model combined with intravital 2-photon imaging of the draining lymph node (LN) to concurrently visualize pathogen-specific CD4(+) and CD8(+) Tcells, we found that early priming of CD4(+) Tcells involved clustering with migratory skin DCs. CD8(+) Tcells did not interact with migratory DCs and their activation was delayed, requiring later clustering interactions with LN-resident XCR1(+) DCs. CD4(+) Tcells interacted with these late CD8(+) Tcell clusters on resident XCR1(+) DCs. Together, these data reveal asynchronous Tcell activation by distinct DC subsets and highlight the key role of XCR1(+) DCs as the central platform for cytotoxic T lymphocyte activation and the delivery of CD4(+) Tcell help.