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

• Activation of T cell subsets after peripheral virus infection is temporally regulated
• CD4+ T cells, but not CD8+ T cells, are activated early by migratory DCs
• CD8+ T cell activation is delayed until LN-resident XCR1+ DCs can prime
• XCR1+ DCs are critical for the delivery of T cell help

SummaryThe dynamics of when and where CD4+ T cells provide help for CD8+ T cell priming and which dendritic cells (DCs) activate CD4+ T cells in vivo 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+ T cells, we found that early priming of CD4+ T cells involved clustering with migratory skin DCs. CD8+ T cells did not interact with migratory DCs and their activation was delayed, requiring later clustering interactions with LN-resident XCR1+ DCs. CD4+ T cells interacted with these late CD8+ T cell clusters on resident XCR1+ DCs. Together, these data reveal asynchronous T cell 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+ T cell help.

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